The polymorphism Pro12Ala in peroxisome proliferator-activated receptorγ2 gene (PPARγ2) has been reported to be associated with diabetic nephropathy (DN) in some studies, though the results remain inconclusive. To explore this relationship between PPARγ2 Pro12Ala polymorphism and the susceptibility for DN, a cumulative meta-analysis was performed in this study.PubMed, Medline, Embase and Web of Science databases have been systematically searched to identify relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.heterogeneity=0.008; P=0.034). In the stratified analysis by ethnicity, significantly decreased risks were found among Caucasians for dominant model , while there was no significant association was found in Asians.18 studies were included in this meta-analysis, involving 3,361 cases and 5,815 controls. The PPARγ2 Ala12 allele was significantly associated with decreased risk of DN based on dominant model . Further large and well-designed studies are needed to confirm this conclusion.http://www.diagnosticpathology.diagnomx.eu/vs/7491348341027320.The virtual slides for this article can be found here:  Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) worldwide, and it is estimated that 20% of T2D patients reach ESRD during their lifetime . The patPPAR-γ2 is a nuclear receptor that serves important roles in intermediate metabolism. The PPARG gene is located on chromosome 3p ,5. The POne putative genetic determinant of DN is the Pro12Ala polymorphism in the gene encoding PPARg. PPARg, a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors, plays a key role in regulating the expression of numerous genes involved in lipid metabolism, metabolic syndrome, inflammation, and atherosclerosis ,7. The PA comprehensive literature search was performed using the PubMed, Medline, Embase, and Web of Science database for relevant articles published (last search updated in May. 2013) with the following key words “PPARγ2”, “polymorphism” and “diabetic nephropathy”. Additional studies were identified by hand searching references in original articles and review articles. Authors were contacted directly regarding crucial data not reported in original articles. The search was limited to human studies. All eligible studies were retrieved, and their bibliographies were checked for other relevant publications. When the same sample was used in several publications, only the most complete study was included following careful examination.The included studies have to meet the following criteria: (1) only the case–control studies were considered; (2) evaluated the PPARγ2 Pro12Ala polymorphism and DN risk; (3) the genotype distribution of the polymorphism in cases and controls were described in details, and the results were expressed as odds ratio (OR) and corresponding 95% confidence interval (95% CI).Major reasons for exclusion of studies were as follows: (1) not for DN research; (2) only case population; (3) duplicate of previous publication; and (4) the distribution of genotypes among controls are not in Hardy–Weinberg equilibrium (P <0.01).Information was carefully extracted from all eligible studies independently by two investigators according to the inclusion criteria listed above. The following data were collected from each study: first author’s name, year of publication, country of origin, ethnicity, source of controls, genotyping method, match, sample size, and numbers of cases and controls in the PPARγ2 Pro12Ala genotypes whenever possible. Ethnicity was categorized as “Caucasian” and “Asian”. When a study did not state which ethnic groups were included or if it was impossible to separate participants according to phenotype, the sample was termed as “mixed population”. We did not define any minimum number of patients to include in this meta-analysis. Articles that reported different ethnic groups and different countries or locations, we considered them different study samples for each category cited above.I2 value, Venice criteria [I2 test included: “I2< 25% represents no heterogeneity, I2= 25–50% represents moderate heterogeneity, I2= 50–75% represents large heterogeneity, and I2 >75% represents extreme heterogeneity”. If results were not heterogeneous, the pooled ORs were calculated by the fixed-effect model  [Crude odds ratios (ORs) together with their corresponding 95% CIs were used to assess the strength of association between the PPARγ2 Pro12Ala polymorphism and DN risk. The pooled ORs were performed for dominant comparison model (Ala-carrier vs Pro/Pro). Between-study heterogeneity was assessed by calculating Q-statistic   and quanstudies) . Otherwistudies) . We alsostudies)  and Eggestudies)  were useStudies relevant to the searching words were retrieved originally. 18 publications addressing the association between PPARγ2 Pro12Ala polymorphism and DN risk were preliminarily eligible ,17-30. Theterogeneity=0.008; P=0.034) . To avoid the influence of heterogeneity among the included studies, subgroup analyses were distinctively carried out according to the ethnicity. In the stratified analysis by ethnicity, significantly decreased risks were found among Caucasians for dominant model , while there was no significant association was found under the same genetic model  , but not found in Caucasian populations .Overall, the Pro12Ala polymorphism was found to be significantly associated with decreased risk of T2D DN    Figure .It is well recognized that there is individual susceptibility to the DN even with the same environmental exposure. Host factors, including polymorphisms of genes involved in this formation of DN may have accounted for this difference. Therefore, genetic susceptibility to DN has been a research focus in scientific community. Recently, genetic polymorphisms of the PPARγ2 Pro12Ala gene in the etiology of DN have drawn increasing attention. Previous results of the studies on the relationship between PPARγ2 Pro12Ala polymorphisms and DN risk were contradictory. These inconsistent results are possibly because of a small effect of the polymorphism on DN risk or the relatively low statistical power of the published studies. A meta-analysis is a powerful strategy because it potentially investigates a large number of individuals and can estimate the effect of a genetic factor on the risk of the disease -35. To bThe present study including 3,361 cases and 5,815 controls from 18 published case–control studies, explored the association between a potentially functional polymorphism, PPARγ2 Pro12Ala and T2D DN risk. We found that there was evidence that the variant genotypes of the PPARγ2 were associated with a significant decreased overall risk of DN. When stratified by ethnicity, Caucasians with the Ala carrier showed a decreased risk of DN compared with those with the Pro/Pro genotype. However, Asians did not show the same results.Some limitations of this meta-analysis should be mentioned. Firstly, bladder cancer is a multifactorial disease that results from complex interactions between many environmental and genetic factors. This means that there will not be single gene or single environmental factor that has large effects on DN susceptibility. Our results were based on unadjusted estimates, while a more precise analysis should be conducted if individual data were available, which would allow for the adjustment by other covariates including age, sex, family history, environmental factors and lifestyle. Secondly, the number of subjects was relatively small, not having enough statistical power to explore the real association. Thirdly, the controls were not uniformly defined. Finally, there were only two ethnic decent populations. So, further large and well-designed studies are needed to confirm this conclusion.This meta-analysis suggests that the PPARγ2 Pro12Ala polymorphism is not a risk factor for developing T2D DN. Moreover, gene–gene and gene–environment interactions should also be considered in future analysis. Such studies taking these factors into account may eventually lead to our better, comprehensive understanding of the association between the PPARγ2 Pro12Ala polymorphism and T2D DN risk.DN: Diabetic nephropathy; HWE: Hardy–Weinberg equilibrium; OR: Odds ratio; CI: Confidence interval; PPARγ2: Peroxisome proliferator-activated receptorγ2 gene.Both authors declared that they have no conflict interest in relation to this study.Lei Wang, Zan Teng, Shuang Cai,Difei Wang, Xin Zhao and Kai Yu drafted the manuscript, and carried out the molecular genetic studies, participated in the sequence alignment, Lei Wang reviewed the manuscript finally. All authors read and approved the final manuscript.


The effects of beverage alcohol (ethanol) on the body are determined largely by the rate at which it and its main breakdown product, acetaldehyde, are metabolized after consumption. The main metabolic pathway for ethanol involves the enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Seven different ADHs and three different ALDHs that metabolize ethanol have been identified. The genes encoding these enzymes exist in different variants , many of which differ by a single DNA building block . Some of these SNPs result in enzymes with altered kinetic properties. For example, certain ADH1B and ADH1C variants that are commonly found in East Asian populations lead to more rapid ethanol breakdown and acetaldehyde accumulation in the body. Because acetaldehyde has harmful effects on the body, people carrying these alleles are less likely to drink and have a lower risk of alcohol dependence. Likewise, an ALDH2 variant with reduced activity results in acetaldehyde buildup and also has a protective effect against alcoholism. In addition to affecting drinking behaviors and risk for alcoholism, ADH and ALDH alleles impact the risk for esophageal cancer. The duration and extent of the body’s exposure to beverage alcohol  is the primary determinant of ethanol’s pleiotropic effects on human health . The timBoth ADH and ALDH exist in different variants with different levels of activity, therefore resulting in different rates of ethanol metabolism. This article discusses how these differences influence a person’s sensitivity to ethanol’s effects and his or her risk of alcohol dependence.ADH1A, ADH1B, and ADH1C genesThe ADH4 gene is expressed almost exclusively in the liver . The physiological substrates for ADH5 (α-ADH) are compounds  formed during the reaction between glutathione and formaldehyde and between glutathione and nitric oxide —that is, sites in which the DNA sequence differs by a single building block  from the reference sequence. Some of these variations result in an altered amino acid sequence of the encoded enzyme and therefore are considered functional or coding SNPs (cSNPs). Detailed functional studies are lacking for all these cSNPs except those that give rise to the ADH1B and ADH1C gene variants .The ADH1B usually are referred to as ADH1B*1 , ADH1B*2 , and ADH1B*3 . The encoded enzyme variants differ significantly in the ethanol concentrations they require for maximal function and in how fast they metabolize the ethanol , with both ADH1B*2 and ADH1B*3 encoding enzymes with faster turnover  than the reference allele , whereas those who carried at least one ADH1B*2 allele had very low BECs, consistent with a more rapid ethanol metabolism by ADH1B*2   and also reduced the maximum number of drinks consumed in one sitting   . It has  sitting . Another < 10−8) . The ADHpulation , as wellpulation . Finallyh Africa .ADH1B*3 allele is relatively common in Eastern African populations, with frequencies of 27 percent among Yoruba, 14 percent among Luhya, and 24 percent among people of African ancestry in the Southwestern United States but only 4 percent among Maasai in Kenya. In contrast, the allele is rare elsewhere and is not found in the European or Asian HapMap samples. Fewer studies of alcohol dependence have been conducted among people of African ancestry, but ADH1B*3 has been shown to be protective against alcohol dependence  has Arg at position 272 and isoleucin (Ile) at position 350, whereas that encoded by ADH1C*2 (γ2-ADH) has glutamine (Gln) at position 272 and valine  at position 350  with one of the amino acid changes at this locus was associated with alcoholism in two GWASs candidate gene substudies on people of European descent, but the difference did not reach statistical significance for genome-wide analyses  (ADH variations are inherited together with nearby SNPs as haplotypes.Many other variations in and around the seven n vitro) , 2011, aADH genes, the ALDH genes are not localized to a single chromosome. Humans have 18 genes encoding for members of the ALDH enzyme superfamily  and by the effects of a functional polymorphism commonly found in East Asian populations (ALDH2*2), in which a critical glutamate is substituted by a lysine residue at position 504 of the precursor protein (487 of the mature protein)   . With bo; rs671) . The ALD percent ), where  percent ), and hoALDH2*2 allele. The KM valuesALDH1A1 gene, and linkage to alcohol-related phenotypes has been found in both European populations  and peo67952887 ). In addeactions , suggestCYP2E1*B5 allele (rs2031920) and alcoholic liver cirrhosis  also contributes to ethanol metabolism, particularly in alcoholics in whom chronic ethanol exposure induces higher expression levels of the enzymes involved. The primary component of the MEOS is cytochrome P450 2E1 (CYP2E1). Increased production of acetaldehyde through this pathway is associated with increased risk for liver damage , presumairrhosis , 2010. TADH and ALDH alleles affect the risk for esophageal cancer. In a meta-analysis of studies (primarily of East Asian populations), the presence of ADH1B*1 was associated with a higher risk for esophageal cancer even in men who drank little or rarely and had a greater effect in heavier drinkers  independently were protective against upper aerodigestive cancers, particularly among heavier drinkers (In addition to affecting drinking behaviors and risk for alcoholism, drinkers . Moreovedrinkers .The onset of the genomics era has initiated a rapid increase in researchers’ ability to find and analyze polymorphisms within the enzymes responsible for ethanol metabolism. In fact, the rate of discovery of polymorphisms in and near these genes far outpaces the ability to functionally characterize them. Future studies of the expression and kinetic properties of the variant enzymes are important. In particular, methodologies for rapidly and accurately determining protein expression levels of specific forms are needed. For example, a commonly used approach to identify individual problems—that is, the use of specific antibodies—has not yet worked with the ADH1A, ADH1B, and ADH1C proteins because these proteins are highly conserved, with their sequence at the protein level more than 93 percent identical; moreover, many of the sequence changes are located within functional sites and not optimally situated for antibody recognition. Knowledge of expression level changes, however, will be critical to develop models for predicting the metabolic consequences of both the currently characterized functional polymorphisms and those that are yet to be discovered.


In the last decade it has been demonstrated that the single nucleotide polymorphism (SNP) at codon 72 of the p53 gene is associated with the risk for development of various neoplasms. MDM2 SNP309 is a single nucleotide T to G polymorphism located in the MDM2 gene promoter. From the time that this well-characterized functional polymorphism was identified, a variety of case-control studies have been published that investigate the possible association between MDM2 SNP309 and cancer risk. However, the results of the published studies, as well as the subsequent meta-analyses, remain contradictory.The tumor suppressor gene MDM2 SNP309 and the functional genetic variant in p53 codon72 (Arg72Pro) and p53 mutation status, we performed a meta-analysis of the risk estimate on 27,813 cases with various tumor types and 30,295 controls.To investigate whether currently published epidemiological studies can clarify the potential interaction between MDM2 SNP309 and tumor susceptibility in the stratified analysis by p53 mutation status .The data we reviewed indicated that variant homozygote 309GG and heterozygote 309TG were associated with a significant increased risk of all tumor types (homozygote comparison: odds ratio (OR) = 1.25, 95% confidence interval (CI) = 1.13-1.37; heterozygote comparison: OR = 1.10, 95% CI = 1.03-1.17). We also found that the combination of GG and Pro/Pro, TG and Pro/Pro, GG and Arg/Arg significantly increased the risk of cancer . In a stratified analysis by tumor location, we also found a significant increased risk in brain, liver, stomach and uterus cancer . However, no association was seen between MDM2 SNP309 serves as a tumor susceptibility marker, and that there is an association between MDM2 SNP309 and p53 Arg72Pro regarding tumor susceptibility. Further studies that take into consideration environmental stresses and functional genetic variants in the p53-MDM2-related genes are warranted.The analyses indicate that  Although the functional differences of these two variants of the p53 protein remain unclear, it has been demonstrated that a single nucleotide polymorphism (SNP) at codon 72 of the p53 gene is associated with the risk for development of various neoplasms. However, in the rest of human tumor types, the p53 gene remains in a wild-type form and its activity is eradicated by its principal cellular inhibitor, murine double minute 2 protein (MDM2) [The p53 protein is a principal mediator of growth arrest, apoptosis, and senescence in response to an array of cellular damage -3. VarioMDM2 gene (rs2279744), known as MDM2 SNP309[MDM2 promoter in cell lines, and consequently enhanced the expression of MDM2 RNA and protein, resulting in a possible attenuation of the p53 pathway [p53 allele mutated) and patients with sporadic soft tissue sarcoma, the presence of the SNP309 G-allele accelerated tumor formation [MDM2 is the primary regulator of p53. MDM2 and p53 regulate each other through a feedback loop. In this mechanism, p53 induces MDM2, and MDM2 then acts as an E3 ubiquitin ligase that exports p53 out of the nucleus and promotes its degradation . MoreoveM2 SNP309. Bond etormation ,11.MDM2 SNP309 and the risk of various types of cancer [MDM2 SNP309 is associated with cancer risk and to investigate the possible interaction between MDM2 SNP309 and p53 mutation status and the p53 codon72 polymorphism.To date, a number of studies have explored the association between f cancer -77, inclf cancer , forty-oMDM2 SNP309 and tumor risk . To perform the search we used the subject terms "MDM2 polymorphism(s) and tumor". Only English-language and Chinese-language papers were included. The references cited in the original studies or review articles concerning the relevant topic were retrieved in order to potentially broaden the search with additional relevant publications.We searched the Pub Med and CNKI databases for all genetic association studies published to date on the MDM2 SNP309 and tumor susceptibility; (b) the study reports genotypic frequencies of MDM2 SNP309 in cancer patients and controls; (c) the genotype of the control population is in Hardy-Weinberg equilibrium. If the study had the same population resource or had overlapping subjects, only the study reporting the largest population was selected. Hence, we included sixty-six studies in our meta-analysis, containing 27,813 cases with different tumor types and 30,295 controls.All studies reporting human associations that met the following criteria, regardless of sample size, were included in this meta analysis; if not, the studies were excluded: (a) the study is a case-control study on the association of p53 mutation status, and interaction with p53 Arg72Pro status  in controls, MDM2 SNP309 and tumor risk. The fixed effect model and the random effect model based on the Mantel-Haenszel method and the Dersimonian and Laird method, respectively, were used to pool data from different studies. If the heterogeneity between studies is absent, these two models provide similar results; otherwise, it is more appropriate to adopt the random effect model. We first compared the tumor risk in the variant homozygote GG and in the heterozygote TG with the wild-type TT homozygote. The ORs and 95% CIs were calculated. The statistical significance of the OR was determined using the Z test. Statistical heterogeneity between studies was assessed with the χ2-based Q test and Ι2, heterogeneity was considered significant when P < 0.1, and Ι2 was used to qualify variation in OR attributable to heterogeneity. Crossover analysis was used for interaction analysis.Odds ratios (ORs) were pooled to evaluate the association between Publication bias was investigated using the funnel plot, a method used to analyze subjective data. To supplement the funnel plot method, we also adopted the liner regression approach proposed by Egger et al. ORs and 95%CIs were generated by meta-analysis using STATA (version 10.0).After screening the titles and abstracts, a total of eighty-two full text articles were reviewed to identify eligibility for our systematic review. According to the inclusion criteria, we found that five articles were meta-analyses -82, two p53 mutation status was detected in tumor cases, but only seven of these studies presented the MDM2 SNP309 genotype distributions according to p53 mutation status [MDM2 SNP309 and p53 codon72 polymorphism on cancer risk; however, only six studies [The detailed characteristics of the sixty-six case-control studies are shown in Additional file n status ,41,54,70 studies ,51,60,72MDM2 309G allele frequency in the different ethnic groups . Interestingly, we also found that the variant heterozygote TG exhibited an increased risk for all tumor types . Significant effects were also found both in the recessive and dominant models  for subjects with the MDM2 309GG and p53 Pro/Pro genotype is larger than the OR (1.96) for subjects with the MDM2 309GG and p53 Arg/Arg or the OR (1.38) for subjects with the MDM2 309TT and p53 Pro/Pro genotype  had been shown to interact with SNP309 in the carcinogenesis of several carcinomas [p53 Arg72Pro and MDM2 SNP309. We found that the OR for subjects with the MDM2 309 GG genotype and p53 72 Pro/Pro genotypes compared to subjects with MDM2 309 TT and p53 72Arg/Arg genotypes (3.38) was larger than the OR for subjects with the MDM2 309GG genotype and p53 72Arg/Arg (1.96) or the OR for those with MDM2 309TT and p53 72 Pro/Pro (1.38). These results suggested a possible interaction effect between the MDM2 309GG and the p53 72 Pro/Pro genotype in increasing the risk of carcinogenesis.In order to incorporate the p53 mutation status while investigating the effect of utations ,41,54,70rcinomas ,51,60,72The strength of our meta-analysis is due to the large number of comparisons included. However, our study does have a limitation: the controls in the studies included were not uniformly defined and thus the results presented here are based upon unadjusted estimates. A more precise analysis could be conducted with estimates adjusted according to covariates such as age, smoking, lifestyle, and environmental factors.MDM2 SNP309 is associated with tumor risk and support the potential interaction effect between the MDM2 SNP309 and the polymorphism of p53 codon72. This investigation could be extended in future studies by incorporating other potential risk factors and p53-MDM2-related genes for tumor development.In summary, our results provide some support for the hypothesis that We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work; there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of the manuscript. The authors indicated no potential conflicts of interest.YW carries out the meta-analysis study and drafted the manuscript. WW participates in the design of the study and performs the statistical analysis. ZY and WW collect and extract the data. PG has been involved in revising the manuscript critically for important intellectual content. BZ conceives of the study, and participates in its design and coordination and helps to draft the manuscript. All authors read and approve the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/11/208/prepubCharacteristics of included studies investigating the association between MDM2 SNP309 and tumor risk.Click here for file


BIRC5, also called as survivin), a novel member of the inhibitor of apoptosis protein (IAP) family, has implications in many types of cancer and is considered as a new therapeutic target. We suppose that genetic variant rs9904341 in the 5′ UTR region of survivin gene may be associated with the development and progression of prostate cancer (PCa) in Chinese population.Abnormal expression of Baculoviral inhibitor of apoptosis repeat-containing 5 . In addition, we observed that PSA ≥ 20 was more frequent in patients carrying GC/CC genotypes than in those with a wild type genotype.Our results indicated that compared with GG genotypes, there was a statistically significant increased risk of PCa associated with those with CC genotypes [odds ratios (ORs) = 1.57, 95%confidence intervals (CIs) = 1.17-2.13, survivin rs9904341 genetic variant may have a substantial influence on the PCa susceptibility and evolution.The functional  It is abundantly expressed in the G2/M phase of the cell cycle, supporting the rapidly dividing cell mechanism, [survivin in conditional knockout mice had shown phenotypes with exaggerated apoptosis, with or without catastrophic mitotic defects [Apoptosis is an essential genetic session which is necessary for the proper development of an organism . The acc) family ,4. It ha) family ,6. Survipoptosis . Besideschanism, . Further defects -16.Prostate cancer (PCa) is a frequently-occurring disease and is the second leading cause of cancer-related deaths of Western males. An analysis of the incidence and mortality of prostate cancer patients showed that approximately 217,730 new cases occurred and 32,050 deaths in 2010 in the U.S. .survivin was invariably up-regulated in human cancers, associated with the resistance to radiation or chemotherapy therapy, and poor prognosis [survivin, though not normally expressed in the normal tissue and secretory epithelial cells of the prostate [survivin was related to the established features of biologically aggressive PCa, such as Gleason score and metastases [survivin appears to be the most promising diagnostic and prognostic markers in monitoring PCa.Previously, accumulating evidences revealed that the expression of rognosis -23.As toprostate , was strprostate -29. Moretastases -32. As asurvivin in PCa, with biological, prognostic and therapeutic implications, we hypothesized the functional single nucleotide polymorphisms (SNPs) in the survivin gene in charge of expression or activity might contribute to the susceptibility and survival of PCa. Recently, the possible associations between the SNPs in the survivin gene and various types of cancer have been investigated in some prior studies [survivin located at the cell cycle dependent elements (CDE) and cell cycle homology regions (CHR) repressor binding site [survivin gene might be modulated by CDE/CHR elements, as potentially implicated in imparting cell cycle periodicity of expression in G2/M [survivin rs9904341 polymorphism in our study of PCa in Chinese to identify if genetic variants in survivin gene may result in the susceptibility and progression of PCa.Given the significant role of  studies -43. Amoning site . Transcr in G2/M . To veri1-2N0M0). Advanced cancer meant the cancer had spread through the prostatic capsule (T3-4NXMX or TXN1MX or TXNXM1). The Gleason score was estimated by pathologists in the hospital by using the Gleason scoring system. Based on the EAU Guidelines on Prostate Cancer and D’Amico’s Risk-Based management of PCa, serum PSA value was classified into two groups PSA > 20 ng/ml and PSA ≤ 20 ng/ml. The participation response rates for both case and control subjects were > 85%.Between September 2003 and January 2010, unrelated male (n = 1375) self-described ethnic Han Chinese were consecutively enrolled from the First Affiliated Hospital of Nanjing Medical University, Nanjing, China. All of the incident sporadic PCa cases (n = 665) were newly diagnosed, histopathologically confirmed and identified by reviewing the medical records that they had no prior history of other cancers. Healthy controls (n = 710) consisted of randomly-selected volunteers, and if they were unrelated cases and age-matched were also ascertained at the First Affiliated Hospital of Nanjing Medical University. Before enrollment, peripheral blood was obtained from every individual. A standard questionnaire through face-to-face interviews by trained interviewers was made to collect demographic data and related factors, including age, race, smoking history, alcohol intake, and family history of cancer. The study was approved by the Institutional Review Board of the Nanjing Medical University, Nanjing, China. At recruitment, written informed consent was obtained from all participants involved in this study. Those subjects who smoked less one cigarette per day and less one year over their lifetime were defined as nonsmokers and the rest as smokers. Lighter or heavier smokers were classified by WHO . The participants who had pack-years value (cigarettes per day/20) × (years smoked) < 20 were considered as lighter smokers, the others  were considered as heavier smokers. Those who drunk at least three times per week for more than 6 months were defined as drinkers; otherwise, they were considered as nondrinkers. Family history of cancer was defined as any occurrence of cancer in first-degree relatives . Disease stage was determined by clinical stage , Gleason score and PSA value. Localized prostate cancer could be detectable clinically on examination, but had not proliferated out of the prostate  according to the manufacturer’s instructions. The primers and probes for rs9904341 G > C as follows: Forward primer, 5′- CGTGCGCTCCCGACAT-3′, reverse primer, 5′- GATGCGGTGGTCCTTGAGAA-3′; Probe G, 5′- FAM-TGAATCGCGGGACC-MGB-3′, Probe C, 5′- HEX-TTGAATCGCCGGACC-MGB-3′. Amplification was executed in 5 μL volumes in the 384-well plate, for 2 min at 50°C,10 min at 95°C, followed by 45 cycles of 95°C for 15 sec and 60°C for 1 min . The ABI 7900HT Real Time PCR system was adopted by the genotyping assay. The SDS 2.4 software was used to automatically collect and analyze the data and to subsequently generate the genotype calls in a blind manner. Four negative controls in each 384-well plate were used for quality control. Samples making up more than 5% were randomly chosen for repeated genotyping, yielding a 100% concordant.Genomic DNA was extracted from the peripheral blood lymphocytes by using the conventional phenol-chloroform method. SNP rs9904341 G > C in the promoter of 2 test. The student’s t-test (for continuous variables) or chi-square test  was performed to estimate the differences in frequency distributions of selected demographic variables, selected variables, and frequencies of genotypes between cases and controls. The associations between survivin SNP rs9904341 and PCa risk were assessed by computing odds ratios (ORs) and 95% confidence intervals (CIs) from unconditional logistic regression analysis with or without the adjustment for potential confounders. The P value < 0.05 was the criterion of statistical significance, and all of the statistical tests were two sided. All of the statistical analyses were dealt with SAS 9.1.3 software , unless indicated otherwise.Deviation of genotype distribution from the Hardy-Weinberg equilibrium (HWE) for SNP rs9904341 amongst controls was calculated by a goodness-of-fit χP = 0.833). However, in comparison with the controls, a crucially higher proportion of the PCa patients smoked , drunk  and had family history of cancer . Specially, the risk of cigarette addictives (> 20 pack-years) was 1.38 times more  than nonsmokers. For 40.9% of these 665 patients, PSA ≤ 20 ng/ml, and for the rest, PSA were > 20 ng/ml. 390 of them were defined as localized stage cancer, but only 275 of 710 had the advanced stage cancer. When stratified according to Gleason score, the percent of Gleason score < 7, = 7 and > 7 was 33.8%, 33.2% and 33.0%, respectively. These variables were further adjusted with multivariate logistic regression models.The demographic characteristics and the clinical information of 665 PCa patients and 710 controls in the study were outlined in Table survivin SNP rs9904341 between PCa cases and controls were summarized in Table P > 0.05). We observed that frequencies of survivin genotypes were significantly different between cases and controls , which principally derived from discrepancy between wild-type GG (22.5% for cases and 28.9% for controls) and variant-type CC (29.5% for cases and 24.5 for controls). In the multivariate logistic regression models with adjustments of age, smoking status, drinking status, and family history of cancer, our results indicated that CC genotype was associated with a significantly increased risk of PCa compared with the GG genotype .Genotyping call rate of rs9904341 was 99.25%. The genotype and allele distributions of survivin rs9904341 polymorphism were presented in Table P = 0.01, adjusted OR = 1.62, 95% CI = 1.12-2.33). However, no association was observed between the evaluated genotypes and subgroups with clinical stage and Gleason score .Stratification analyses of age, smoking status, drinking status, pack-years of smoking and family history of cancer with the genotypes of survivin is studied to make clear of the susceptibility and manifestation of clinicopathological characteristics of PCa in Chinese population. This is the first investigation done so far to evaluate the role of the SNP (rs9904341) in the survivin gene pertaining to the risk and progression of PCa.Currently, the role of SNP rs9904341 in the promoter region of survivin polymorphism and the risk of PCa are biologically plausible. It is broadly accepted that PCa’s resistance to apoptosis is associated with an alteration in the expression of pro-apoptotic [Survivin, as an apoptotic inhibitor, plays a significant role in the apoptosis pathway and cell proliferation [survivin was prominently over-expressed in various human cancers [et al. observed that increased IAP (including survivin) expression occured early in the pathogenesis of PCa [et al. demonstrated that survivin was associated with PCa cell proliferation [survivin made a crucial contribution to apoptotic resistance in PCa either in vitro or in vivo [Our results revealing the association between this poptotic  and antipoptotic . Surviviferation . Growing cancers , paralle cancers . With res of PCa . Koike eferation . In addi in vivo ,47.survivin, affects transcriptional activity by modifying the binding motif of the CDE/CHR repressor which leads to the measurable and functional discrepancy in survivin expression. This supposition has been vigorously advocated by other investigators. Xu et al. firstly demonstrated that the presence of mutation including rs9904341 polymorphism was correlated with increased survivin expression at both mRNA and protein levels in some cell lines [survivin expressed by homozygous for the -31CC survivin genotype were approximately 1.6 times higher than those with the GG/GC genotypes [survivin mRNA and protein expression level was observed in bladder cancer cell with an increased number of -31C allele by immunohistological evaluation and reverse transcriptase-PCR [surviving probably contributed to the susceptibility of PCa, and our finding confirmed this hypothesis. Moreover, according to the Hapmap database, there was another polymorphism rs8073069 in complete linkage disequilibrium with rs9904341, so we only selected rs9904341 to genotype and analyze.Numerous epidemiological studies, such as case–control, cohort and genome wide association studies (GWAS), have exhibited the role of low-risk genetic variants in susceptibility to PCa. In our present research, an increased risk of PCa was observed among the individuals carrying C allele compared with those carrying G allele, as evidenced by the data obtained in previous studies of urothelial carcinoma , nasophall lines . Jang etll lines . Nikiteaenotypes . Habuchitase-PCR . Taking survivin was considered to be a marker for aggressive PCa and signaling a poor prognosis [It is well known that PCa is a complex malignancy caused by multifactor: age, gene or environment. In stratified analyses, we observed that the effect of rs9904341 polymorphism on the risk of PCa was overstressed among nondrinkers, nonsmokers and those without a family history of cancer, indicating that this polymorphism was an independent risk of PCa and the interaction of gene-environment might be very weak in the subgroups. Furthermore, a line of studies have manifested that the over-expression of rognosis -32. Accorognosis ,49-51. Tsurvivin polymorphism vary with ethnicity compared with the published data. In the controls of our study, the frequencies of GG, GC, CC genotypes in rs9904341 are 28.9%, 46.6%, 24.5%, respectively, which is similar to the date derived from some previous studies on Asian population [Interestingly, our results showed that the genotype distributions of the pulation ,41,42,49Additionally, we are aware of a few limitations in our study, some of which cannot be overcame . First, -based on the patients and the control group randomly from the same hospital, we cannot completely rule out the inherent selection bias. Nevertheless, in order to minimize potential biases, we have made a rigorous epidemiological design of study subjects and more statistical adjustments for known risk factors. Second, our study lacks detailed information including environmental exposure and survival data, and our sample is medium-sized, which may weaken the statistical power of this study. Under the current sample size, we have 80% power at a 0.05 significance level to detect an OR of 1.4 or higher and 0.69 or lower with an exposure frequency of 24.5%. In addition, our conclusions are in accordance with the meta analyses (3329 cases and 3979 controls) in regard to the association between rs9904341 polymorphism and the risk of cancer performed by Mittal . Third, survivin is a genetic susceptibility factor for the pathogenesis and progression of PCa in Chinese population. The observations of the present study are valuable to improve our understanding of the role of survivin in PCa. However, it is necessary that additional studies with more detailed data on environmental exposure and survival data of more samples and functional characterizations are needed to confirm our results, particularly in PCa.In summary, our current results provide the primary evidence that the polymorphism rs9904341 in the promoter of The authors declare that they have no competing interests.JC, CQ, QC, PS, JL, CY were responsible for the study design. JC, XC, HZ, PL, JZ, HC were involved in data acquisition and analysis and performed the Taqman experiments. Statistical analyses, data interpretation and manuscript drafting were done by CQ, XJ, XM, MW, ZZ. All authors critically reviewed and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/13/356/prepub


APOA5) gene variants are genetic determinants of the concentration of triglycerides, which are a known risk factor for coronary heart disease (CHD). Using the standardized coronary angiography method, 290 CHD patients and 198 non-CHD controls were recruited from Ningbo Lihuili Hospital. In addition, 331 unrelated healthy volunteers were recruited as healthy controls from Ningbo Ximen Community residents. Three variants of the APOA5 gene, S19W, -1131T>C and 553G>T, were analyzed for their association with CHD. Under a dominant inheritance model, -1131CT>C was shown to be a CHD risk factor . The single nucleotide polymorphism, 553G>T, was found to correlate with the severity of CHD in males (P=0.032). Meta-analysis showed that -1131T>C was significantly associated with CHD (P<0.0001). By contrast, negative correlations with CHD were observed for S19W and 553G>T. In the present case-control study, APOA5 gene variants were not found to correlate with the risk of CHD in the populations studied; however, -1131CT>C was shown to be a CHD risk factor under a dominant inheritance model. Meta-analysis showed a significant contribution of -1131T>C to the risk of CHD, implying an ethnic difference in APOA5 gene variants.Previous studies have shown that apolipoprotein A5 ( Coronary heart disease (CHD) is a severe condition in which plaque builds up inside the coronary arteries. Over time, plaque hardens and narrows the coronary arteries, eventually leading to myocardic infarction and mortality. Triglycerides (TGs) are the major components of plaque and aberrant levels of TGs significantly correlate with the risk of CHD . IncreasAPOA5) gene variants, including -1131T>C (rs662799) and S19W (rs3135506). These genetic variants have been significantly associated with TG levels (APOA5 gene in the early-onset CHD group (43.2%) has been observed to be significantly higher than that in a control group (33.0%)  is a key regulator of TG levels ,6 and apT>C rs66299 and S1G levels . TG leveT>C rs66299 and S1G levels . In addi (33.0%) . In the  (33.0%) . Despite (33.0%) ,12. In a (33.0%) . However studies ,16. Stud studies . The 19WAPOA5 gene variants, -1131T>C, S19W and 553G>T, are associated with CHD in the populations studied and to evaluate the contribution of APOA5 gene variants to CHD in various ethnic populations by meta-analysis.The aim of the current study was to assess whether the A total of 819 unrelated individuals were recruited for the case-control study. These included 290 CHD cases, 198 non-CHD controls and 331 healthy controls. CHD cases were patients with >50% coronary artery occlusion of one or more major coronary arteries  or a his® dsDNA assay kit . Amplification was performed on the Geneamp® PCR System 9700 Dual 384-Well Sample Block Module  for polymerase chain reaction (PCR). Primers for the single base extension reaction are shown in ® platform  according to the manufacturer’s instructions  and was quantified using the Quant-iT™ PicoGreenAPOA5 gene variants and CHD was conducted in electronic databases, including the Chinese National Knowledge infrastructure, PubMed, Embase, SpringerLink and ScienceDirect, between 2001 and 2012. Specific combinations of keywords were used for the following Medical Subject Heading terms, including ‘coronary heart disease’, ‘coronary artery disease’ or ‘myocardial infarction’ combined with ‘APOA5’, ‘apolipoprotein A5’, ‘C56G’, ‘S19W’, ‘-1131T>C’ or ‘553G>T’ and ‘single nucleotide polymorphism’, ‘SNP’ or ‘genetic association’. All studies were considered eligible if they aimed to investigate the correlation between APOA5 and the risk of CHD. For meta-analysis, studies with one of the following conditions were excluded: i) Studies lacking controls, ii) a lack of detailed main allele or genotype information and iii) duplicate publications.A search of the studies on APOA5 gene variants was measured by an online calculator (http://www.oege.orgsoftware/cubex/). Haplotype frequencies were inferred by Arlequin program version 3.5 based on the expectation-maximization algorithm. The odds ratio (OR) with 95% confidence interval (95% CI) was calculated by an online tool (http://faculty.vassar.edu/lowry/odds2x2.html). The statistical power of the study was calculated by the PS power and sample size calculation software version 3.0.43  was analyzed by Arlequin program version 3.5 . The alln 3.0.43 . The corSNP S19W was monomorphic in samples of the current study and thus, discarded from further analysis. SNPs -1131T>C and 553G>T were consistent with HWE (P>0.05). As shown in The severity of CHD was defined by the number of coronary arteries with >50% coronary artery occlusion. A logistic regression test was performed between the 2 variants and the severity of CHD in all cases and in a gender-stratified manner. The results indicated that 553G>T correlated with CHD severity in males ; P=0.032APOA5 gene variants and the risk of CHD were retrieved from the online databases. Among them, 9 studies were excluded from the current meta-analysis as they focused on other APOA5 variants . Due to the high heterogeneity of these studies, the groups were divided into 2 ethnic subgroups, European and Asian. A significant heterogeneity was observed among Europeans  in contrast to minimal heterogeneity among Asians . A significant association between -1131T>C and CHD risk was observed in European individuals  and Asian subgroups . A significant difference was observed between the 2 subgroups . Funnel plot analysis did not reveal publication bias . Due to the moderate heterogeneity, the random effects analysis model was selected for meta-analysis . An outlier OR-value was observed in 1 study . The results showed that S19W had no significant association with CHD . Funnel plot analysis did not reveal publication bias  activity . The frequency of -1131CT>C in non-CHD controls and healthy controls was 0.380 and 0.376, respectively, which is close to 0.267 in HapMap-HCB and 0.291 in HapMap-JPT (http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=662799). A lower frequency of -1131C was observed in Europeans (0.017 in HapMap-CEU). This is in agreement with the current heterogeneity test results in the meta-analysis.SNP -1131T>C is located in the proximal promoter of the ulinemia . A numbeulinemia ,10,32. Hulinemia ,7,33,34.s of TGs , were nos of TGs . The curSNP 553G>T is a rare APOA5 gene variant that has been studied in Han Chinese populations ,14,29,36et al observed a 4.7% prevalence of 19W in the CHD cases, while in Chinese populations, 19W was not observed (0%) , thus providing an explanation as to why S19W was monomorphic in the samples, including 290 CHD cases, 198 non-CHD controls and 331 healthy controls. Liu ved (0%) ,44. The ved (0%) . Howeverved (0%) . The curved (0%) ,16,36–38In summary, the current case-control study shows that the -1131CT>C gene is a CHD risk factor in the populations studied and this association was further supported by meta-analysis. The case-control study has <80% statistical power (the strongest power observed for -1131T>C was 58.8%). An improved case-control investigation with larger sample sizes and a balanced gender structure is required in the future.


P = 0.016). Moreover, in dominant model (DD frequency versus DI+II frequency) there was a significant relation between DD genotype and preeclampsia (P = 0.006). D allele frequency was 64.6% in preeclampsia while it was 56.1% in controls (P = 0.062). In conclusion, there was significant difference in genotype distribution between preeclampsia and controls.Placental, immune and genetic factors are thought to play an important role in preeclampia (PE)'s pathophysiology. Angiotensin-Converting Enzyme (ACE) plays a vital role in the renin-angiotensin-system (RAS) which regulates blood pressure by converting angiotensin I into a powerfull vasoconstrictor angiotensin II. A deletion polymorphism  has been reported to be associated with elevated ACE activity. The aim of the this study was to investigate whether there is an association between angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism and PE. In this study, 120 preeclamptic and 116 normotensive Turkish pregnant women were genotyped for ACE I/D polymorphism and the distribution of genotype and allele frequencies of this polymorphism in preeclampsia and controls were evaluated. Codominant, dominant and recessive models were appplied in ACE gene I/D polymorphism. In the codominant model, DD genotype was found significantly more frequent in preeclampsia than controls ( Preeclampsia (PE) is a disorder that occurs in women with a new-onset of hypertension and proteinuria after 20 weeks of pregnancy. It plays an important role in perinatal mortality and morbidity, as well as maternal mortality –8. It afAngiotensin-converting enzyme  plays a vital role in the rennin angiotensin system (RAS) which regulates blood pressure by converting angiotensin I into a powerful vasoconstrictor angiotensin II. High ACE activity can contribute to hypertension because of its vasoconstriction effect , 14. An The aim of the study was to investigate whether there is an association between ACE intron 16 I/D polymorphisms and PE.Written approval was obtained from the Ethics Committee of Cukurova University Hospital and Baskent University, and all patients gave their informed consent before peripheral blood samples were taken. Information was enrolled retrospectively about one hundred twenty (120) preeclamptic women and one hundred fourteen (114) normotensive women with no history preeclampsia who delivered at two university hospitals located in Adana  between September 2009 and August 2010. PE cases included both severe and mild PE, and all of them were early-onset cases (after 20 weeks). A total of 234 patients were studied. Clinical characteristics of the study population are reported in Preeclampsia was defined using the criteria of the National High Blood Pressure Education Program Working Group: (1) increase of 30 mm Hg or greater of systolic blood pressure, (2) increase of 15 mm Hg or greater of diastolic blood pressure (both criteria 1 and 2 refer to before and after 20 weeks of gestation), (3) if previous blood pressure was not known, a blood pressure must be ≥140 mm Hg for systolic and ≥110 mm Hg for diastolic after 20 weeks of gestation, (4) in addition to blood pressure, proteinuria was defined as the excretion of 0.3 g/L (1+ on a dipstick) or greater . Women wμL, using 200 ng genomic DNA, 25 mM dNTPs, 10 pmol of each primer, 1 U Taq DNA polymerase (Vivantis), and 2.5 μL ViBuffer S (Vivantis). PCR conditions were 94°C for 5 minutes, followed by 30 cycles at 94°C for 1 minute, 58°C for 1 minute, 72°C for 2 minutes, and a final step at 72°C for 4 minutes.Maternal DNA was isolated from peripheral venous blood leukocytes using standard salting out method as previously described . ACE intμL with the same reagents of the first amplification reaction. PCR conditions were 94°C for 5 minutes, followed by 40 cycles at 94°C for 1 minute, 60°C for 75 seconds, 72°C for 1 minutes, and a final step at 72°C for 10 minutes.To avoid the misidentification of DI genotypes as DD, a second PCR was performed with the same antisense primer as in the first and different sense primer as 5-TTT GAG ACG GAG TCT CGC TC-3′ that generates a 408 bp fragment only in the presence of the I allele. The second PCR was carried out in a total volume of 25 P < 0.05. In the ACE I/D polymorphism, data were analyzed under three models: a codominant, a dominant, and a recessive model.PCR products were analysed by 2% agarose gel after staining by ethidium bromide. Statistical analyses were carried out with the SPSS version 15.0. Pearson's chi-squared test was used for the statistical evaluation of the individual allele and genotype frequencies. The level of statistical significance was defined as The clinical characteristics of the study population are shown in P = 0.016). Moreover, in the dominant model (DD frequency versus DI+II frequency), the difference between the two groups was found statistically significant (P = 0.006). The ACE D allele frequency was 64.6% in preeclampsia and 56.1% in controls, and the difference was not found statistically difference (P = 0.062).The genotype distributions and allele frequencies for ACE I/D polymorphism were summarized in The present study showed an association between ACE DD genotype and preeclampsia in Turkish population. In the analyzed Turkish population, PE cases included both severe and mild PE and all of them were early-onset cases (after 20 weeks). On average, deliveries occurred about 3 weeks earlier in the preeclamptic women than in the controls.The results of previous studies on association of ACE I/D polymorphism with preeclampsia were conflicting presumably attributable to differences in study population, genetic backgrounds, and size of study groups. Some studies showed significantly higher incidence of DD genotype and/or D allele in preeclampsia and/or pregnancy-induced hypertension –19. On tIn the present study, for ACE I/D polymorphism analysis, we used three models: codominant, recessive, and dominant models which were used in a study on Caucasian population . We deteIn conclusion, although our results show an association between the ACE DD genotype and preeclampsia in the analyzed Turkish population, further studies using a larger number of subjects and analyses that include genetic, environmental, and other potential factors are needed to confirm these results.


COL1A2) gene, which has been identified as a risk variant for intracranial aneurysm, with nAMD and PCV in a Han Chinese population.We have previously documented that neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) have multiple different clinical and genetic characteristics. In this study, we investigated the association of rs42524 in the alpha-2 type I collagen =0.04253, odds ratio=0.5285 ], but not with PCV . The pCOL1A2 confers different levels of susceptibility to nAMD and PCV.The rs42524 polymorphism is a risk allele for nAMD in a Han Chinese population. rs42524 in  Polypoidal choroidal vasculopathy (PCV) is characterized by polyp-like terminal aneurysmal dilations with or without branching choroidal vessels -4. AlthoAlthough the genetics of nAMD have been well studied, investigations into the genes encoding the structural proteins involved in this disease are limited -16. HoweCollagen destruction can result in a decrease in vessel integrity and an increase in vessel permeability . Type I COL1A2) gene is located in the 7q22.1 locus and encodes the pro-alpha 2 chain protein. The rs42524 polymorphism in COL1A2 results in an amino acid substitution, Ala to Pro, at amino acid position 459 and therefore influences the integrity of type I collagen, decreases vessel wall rigidity, and eventually causes the destruction of blood vessel walls , but not with PCV . The odds ratio for the G allele of rs42524 was 0.53  for nAMD and 1.21  for PCV  with an effect size index of 0.2 (corresponding to a weak-to-moderate gene effect). The degrees of freedom were 1 for allelic frequencies and 2 for genotype frequencies. The statistical power to detect changes in allelic frequencies for the nAMD and PCV groups versus the controls was 87.98% and 93.21%, respectively, and the power to detect changes in genotype frequencies was 80.66% and 88.01%, respectively.Both nAMD and PCV are leading causes of blindness and visual impairment in the elderly population. Recently, many studies have found that the two possess different genetic backgrounds, clinical characteristics, and prognoses. These results indicate a strong possibility that PCV and nAMD have different pathogenic mechanisms -34.ELN) and susceptibility to the two diseases [In recent analyses of human PCV and AMD specimens, several investigations have suggested a possible role for vessel destruction as a pathogenic mechanism in PCV and AMD. Other studies have sought to identify the related SNPs and finally identified a relationship between elastin  in 9p21 shared between the two [COL1A2 gene extensively for suspected SNPs and found a particularly strong association between the polymorphism rs42524 and IA under a dominant model [COL1A2 and IA in a Han Chinese population [We previously found that PCV was most likely associated with IA and have documented a variant  in Caucasian individuals [COL1A2 expression suppressed neovessel growth and curtailed CNV fibrosis [COL10A1 (rs1999930) in Caucasian individuals, finding that the development of advanced AMD might be caused in part by extracellular collagen matrix pathways [The results of our case-control study demonstrated that  studies ,45. To dividuals . Howeverpathways .rs42524, however, is not associated with PCV. This differential susceptibility of PCV and nAMD agrees with previous studies that found little-to-no overlap between PCV and nAMD susceptibility genes [SERPING1 polymorphisms [rs10757278) on chromosome 9p21 was reported to be associated with PCV, but not with nAMD, in a Chinese population [We found that ty genes ,12. Our orphisms . Additiopulation . Taken tThe main limitations of our study included the relatively small sample size and the fact that not all of the collagen genes were surveyed. These results need to be confirmed in a larger cohort and with comprehensive investigations of all of the collagen genes.COL1A2 (rs42524) polymorphisms in PCV and nAMD. We found that rs42524 is significantly associated with nAMD, but not with PCV. This finding may imply that COL1A2 gene polymorphisms play an important role in the development of nAMD. Finally, we discovered that the G allele of rs42524, rather than the C allele, confers nAMD risk.In conclusion, we investigated the association of


The purpose of this meta-analysis is to define the effect of p53 Arg72Pro polymorphism on hematological malignancies risk.Previous studies on the association of p53 Arg72Pro polymorphism , including nine studies on leukemia , three studies on lymphoma , and one study on myeloma. The overall results suggested that p53 Arg72Pro polymorphism was not associated with hematological malignancies risk. In stratified analyses, significantly increased non-Hodgkin lymphomas risk was found in p53 Arg72Pro polymorphism heterozygote model  and dominant model , but no significant association was found between leukemia risk and p53 Arg72Pro polymorphism. Further studies showed no association between leukemia risk and p53 Arg72Pro polymorphism when stratified in subtypes of leukemias, ethnicities and sources of controls.Through searching PubMed databases (or hand searching) up to April 2012 using the following MeSH terms and keywords: “p53”, “codon 72” “polymorphism” and “leukemia”, or “lymphoma”, or “myeloma”, thirteen were identified as eligible articles in this meta-analysis for p53 Arg72Pro polymorphism may contribute to susceptibility to non-Hodgkin lymphomas.This meta-analysis indicates that the  Hematological malignancies derived from either of the two major blood cell lineages: myeloid and lymphoid cell lines, include leukemias, lymphomas, myeloma, myelodysplastic syndromes and myeloproliferative diseases. Lymphomas, lymphocytic leukemias, and myelomas are from the lymphoid line, while acute and chronic myelogenous leukemia, myelodyplastic syndromes and myeloproliferative diseases are myeloid in origin. Generally, the overall incidence of hematological malignancies appears to be rising in Western countries but it is very difficult to describe on their epidemiological behavior in a consistent way p53 mutations are commonly found in different cancers and thought to be associated with carcinogenesis p53 seem to have a modest effect on cell phenotype, leading to different patterns of cancer susceptibility p53 gene locates on chromosome 17p13 and contains 11 exons. The common p53 polymorphisms include p53 codon 72 , deletion of 16 bp in intron 3  and IVS6+62A>G  polymorphisms p53 codon 72 (Arg72Pro) polymorphism is most widely studied in different cancers The tumor suppressor p53 plays a pivotal role in response to genotoxic insults from endogenous or environmental agents by orchestrating a diversity of pathways from activation of cell signaling transduction, transcriptional responses, DNA repair to regulation of cell cycle progression and apoptosis p53 codon 72 polymorphism is located in exon 4 with CGC to CCC transition, leading to an arginine-to-proline amino-acid substitution in amino-acid position 72 p53 Arg72Pro polymorphism and hematological malignancies risk, however, these studies revealed an inconsistent conclusion, probably due to the relatively small size p53 Arg72Pro polymorphism and hematological malignancies risk in this study.The p53 codon 72 polymorphism with hematological malignancies, we conducted a literature search in the PubMed databases up to April 2012 using the following MeSH terms and keywords: “p53”, “codon 72” “polymorphism” and “leukemia”, or “lymphoma”, or “myeloma”. Additional studies were identified by a hand search from references of original studies or review articles on this topic. Eligible studies included in this meta-analysis had to meet the following criteria: (a) an unrelated case-control study, if studies had partly overlapped subjects, only the one with a larger sample size was selected, (b) available genotype frequency, (c) sufficient published data for estimating an odds ratio (OR) with 95% confidence interval (CI) and (d) the genotype frequencies in the control group were consistent with Hardy-Weinberg equilibrium (HWE).To identify all articles that examined the association of Two investigators independently extracted data and reached a consensus on all of the items. The following information was extracted from each study: first author, year of publication, country of origin, ethnicity, number of cases and controls, genotype frequency for cases and controls, characteristics for cases, sources of DNA and genotyping methods. Different ethnicity descents were categorized as Asian and Caucasian.p53 Arg72Pro polymorphism and hematological malignancy risk. We first estimated the risks of the Arp/Pro and Pro/Pro genotypes on hematological malignancies, compared with the reference Arg/Arg homozygote, and then evaluated the risks of (Arp/Pro+Pro/Pro vs. Arg/Arg) and (Pro/Pro vs. Arg/Arg + Arp/Pro) on hematological malignancies, assuming dominant and recessive effects of the variant Pro/Pro allele, respectively Hardy-Weinberg equilibrium (HWE) was tested by the chi-square test. Crude ORs with 95% CIs were used to assess the strength of association between the 2-based Q-test. The summary OR estimate of each study was calculated by the random-effects model (the DerSimonian and Laird method).Stratified analyses were also performed by types of hematological malignancies, ethnicities and sources of controls. Potential heterogeneity was checked by the χt test was performed to determine the significance of the asymmetry, and a P value of <0.05 was considered a significant publication bias. All analyses were done with Stata software , using two-sided P values.Publication bias was investigated by funnel plot, and an asymmetric plot suggested possible publication bias. The funnel plot asymmetry was assessed by Egger’s linear regression test. The in vitro cell biology studies p53 genotype distribution were listed in Nineteen abstracts were retrieved through the search “p53”, “codon 72”, “polymorphism” and “leukemia”, and eight studies were identified as eligible studies. Out of the nineteen, seven studies were excluded given that they have not included controls, did not report genotype frequency for controls in their study designs, or reported other diseases p53 codon 72 polymorphism was performed using polymerase chain reaction (PCR), polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP), Taqman PCR, or single-strand conformation polymorphism (SSCP) analyses on the genomic DNA from the human blood samples. For ethnic distribution, there were seven studies of Caucasian descent, and six of Asian origin. For the nine studies on leukemia, there were five studies on acute myeloid leukemia (AML) and four studies on others including acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL) and chronic myeloid leukemia (CML). As to ethnic distribution of the leukemia patients, there were five studies of Asians and four studies of Caucasians.The genotyping for p53 Arg72Pro polymorphism was not associated with a hematological malignancies risk, and this negative association maintained in some subgroup analyses such as ethnicities and sources of controls  in all four models (p53 Arg72Pro polymorphism heterozygote (Arg72Pro) was significantly correlated increased lymphomas risk   (p53 Arg72Pro polymorphism and NHL risk.controls . When str models . However02–1.35) , and thi03–1.34) . Actuallp53 Arg72Pro polymorphism and leukemia risk when stratified by the ethnicities, sources of controls, and leukemia types. The results showed that the p53 Arg72Pro polymorphism was not associated with leukemia either in Asians or in Caucasians, and this negative association maintained in other subgroup analyses such as leukemia types and sources of controls . The funnel plot can be misleading Begg’s funnel plot and Egger’s test were performed to assess the publication bias of literatures. The shapes of the funnel plots did not reveal any evidence of obvious asymmetry (Data not shown). Then, the Egger’s test was used to provide statistical evidence of funnel plot symmetry. The results still did not show any evidence of publication bias , nor associated with leukemia risk (five studies) p53 codon 72 Pro allele on leukemia was found in Asians even with a small number of studies (331 cases and 437 controls) p53 Arg72Pro polymorphism was not associated with hematological malignancies or leukemia risk. However, with more than double leukemia cases, we did not found an association between p53 Arg72Pro polymorphism and leukemia risk in Asians (682 cases and 767 controls). We need to point that our meta-analysis study included all the cases from Takeuchi et al. study as leukemia patients, which may introduce bias since there were a few cases of lymphoma patients p53 Arg72Pro polymorphism and leukemia risk in Asians and further studies with larger numbers of participants are needed to clarify this association.Previous meta-analysis showed that p53 codon 72 Arg>Pro polymorphism and risk of AML (n = 5), and risk of other types of leukemia (n = 4)  . Future p53 Arg72Pro polymorphism and lymphoma risk p53 Arg72Pro polymorphism and increased risk of all lymphoma  , and between p53 Arg72Pro polymorphism and increased risk of NHL   (Data not shown). This was consistent with our data that showed significant association between p53 Arg72Pro polymorphism and increased NHL risk based on limited three studies. However, this meta-analysis has limitation by including indolent and aggressive lymphomas in the same group since pathogenetic mechanisms of different types of lymphomas are different. Therefore, additional well-designed large studies were required to validate the association between p53 Arg72Pro polymorphism and increased risk of lymphomas.Recently, six studies were conducted to examine the association between p53 polymorphisms have not been studied, the potential interactions between p53 Arg72Pro polymorphism and other genetic polymorphisms, including those in Murine double minute 2 (MDM2), p73, p21 and Glutathione S-transferase, which are involved in DNA damage repair, apoptosis, cell cycle control, or detoxification of xenobiotic compounds, were found in hematological malignancies The interaction of different polymorphisms in the same gene, or between different genes, might contribute to hematological malignancies risk. Although the combined effects of different p53 Arg72Pro polymorphism was observed among these studies. The heterogeneity may be due to various factors, such as diversity in the population characteristics, differences in the number of cases and controls, genotyping methods and study design. Between-study heterogeneity was detected by restricted maximum likelihood-based random-effects meta-regression analysis. Because the number of included studies was limited, we conducted univariate meta-regression model firstly, variables with significant P values ≥0.1 were then entered into the multivariable model. Ethnicity, MAF, source of controls, sample size, publication years and disease types were taken into consideration, and none of these factors showed an evidence of source of heterogeneity (Heterogeneity for the ogeneity . To elimp53 Arg72Propolymorphism and lymphoma (non-Hodgkin lymphoma) risk, but not leukemia risk. However, the number of studies included for our meta-analysis is very limited, and studies based on larger well-designed populations are still needed to clarify the different effects of the p53 Arg72Pro polymorphism in different types of hematological malignancies. Also, studies examining the combined effects of different p53 polymorphisms or different polymorphisms of p53 related genes  should be investigated.In conclusion, we found significant associations between the Figure S1Contour-enhanced funnel plot for publication bias analysis.(DOC)Click here for additional data file.Table S1Clinical and demographic characteristics of the patients in each study.(DOC)Click here for additional data file.Table S2p53 Arg72Pro polymorphism genotype distribution of each study included in the meta-analysis.(DOC)Click here for additional data file.Table S3Meta-regression analysis.(DOC)Click here for additional data file.


Cataract is the leading cause of blindness worldwide. Many observational studies assessed the relationship between postmenopausal hormone replacement therapy (HRT) and risk of cataract development, but the reported results were controversial. The aim of present meta-analysis was to evaluate the association of postmenopausal hormone replacement therapy with risk of cataract development.The eligible observational studies, including cross-sectional, case–control and cohort studies, were identified by searching PubMed and Embase during March of 2013. Either a fixed- or a random-effects model was used to calculate the pooled odds ratio (OR) with its 95% confidence interval (95%CI). Subgroup analysis on cataract types was performed.A total of four cohort and five case-control or cross-sectional studies were finally included into this meta-analysis. Overall, a significant decreased risk of developing any type of cataract was found in ever HRT group as compared with non-HRT group among cohort studies  and case-control or cross-sectional studies . Subgroup analysis on cataract types determined that the significantly decreased risk of nuclear cataract in current HRT group  and also a critically reduced risk of nuclear cataract in ever HRT group  were found among case-control or cross-sectional studies, as compared with non-HRT group. No association of HRT with risk of cortical and posterior subcapsular cataract was observed.The results of present meta-analysis indicate that postmenopausal hormone use may play a protective role in cataract development. Cataract is the major cause of visual impairment and blindness in older adults in the world . As the Hormone replacement therapy is widely used in the treatment of menopausal symptoms , althougThe meta-analysis was performed, according to the PRISMA in systematic review and meta-analysis . PubMed The following data were extracted independently by two authors (K. Lai and J. Cui) from each study : first author’s name, year of publication, country, study period, study design, sample size, age, cataract definitions and grading, HRT status, adjusted variables, and OR/RR values with 95% CI. The results were compared, and conflicting evaluations were discussed among all authors and resolved with consensus. HRT status was divided into current HRT, past HRT and ever HRT. Current HRT had a history of HRT with HRT prescription used currently. Past HRT had a history of HRT with no current HRT prescription. Ever HRT had a history of HRT regardless of current HRT use. As the outcome of interest, cataract is a disease presented with opacity in the lens or capsule of the eye, which leads to a decreased vision. Cataract mainly includes three subtypes, i.e. cortical cataract, nuclear cataract and post subcapsular cataract (PSC). The patients were diagnosed through examination at a slit lamp by ophthalmologists according to grading systems. Our primary analysis compared the risk of cataract between ever HRT users and never HRT users. Several studies did not provide an overall OR/RR for ever HRT users, but showed the separate adjusted odds ratio of different duration of postmenopausal hormone use or HRT status (past and current). And some studies did not report an OR/RR/HR for any type of cataract, but for subtypes . For reason given above, Jan Hamling’s method  was used2 score [2 is > 50%, substantial heterogeneity was detected. The fixed-effects model (the inverse variance method [OR with its 95%CI was used as a common measure for the association of HRT with risk of cataract across studies. The RR was directly considered as OR. Cochran's Q-statistic and I2 score  were utie method ) was usee method ) was useSubgroup analysis was conducted regarding the association of HRT status (past and current use) with risk of cataract subtypes , respectively. P < 0.05 or P<0.01.Potential publication bias was assessed by the Egger’s linear regression test  and the The search strategy retrieved 96 unique citations from MEDLINE (PubMed) and EMBASE databases. Of these, 76 were excluded after reviewing titles and abstracts, 20 articles for full-text review were left. In this review, 11 articles were excluded for following reasons: one article was a lens transmittance study , one artThe characteristics of the included studies were presented in P<0.05). But there was no significant difference for developing any type of cataract in past HRT group , current HRT group , as compared with non-HRT group. There was no substantial heterogeneity among the included studies . No publication bias was found among the four included studies .In four ,38–40, tP=0.233, I2=31.4%; past HRT group: P=0.204, I2=38.0%; current HRT group: P=0.804, I2=0.0%). Publication bias was found among the four included studies by the Egger’s linear regression test (P=0.003), but not by the Begg’s rank correlation test (P=0.296).Three ,38,40, tP=0.539, I2=0.0%; past HRT group: P=0.319, I2=0.0%; current HRT group: P=0.412, I2=0.0%). No publication bias was found among this subgroup .Three ,38,40, tP=0.090, I2=65.2%). The summary OR was 0.67  with a random-effects model.Two ,40 studiP<0.05). Substantial heterogeneity was observed . Further scrutiny indicated that the heterogeneity shifted from P=0.079 to P=0.582 by Q test and I2 score shifted from 55.8% to 0.0% when the only study conducted in Asia with a small sample size  was excluded . No significant publication bias was found among the four included studies .Four ,16,19,41P<0.01), but not in past HRT group , as compared with non-HRT group .Three ,16,19 stRT group . There wP<0.01) and a critically decreased risk in ever HRT group , but not in past HRT group , as compared with non-HRT group . No significant publication bias was found among the three included studies .Three ,16,19, tRT group . There wP=0.429, I2=0.0%; past HRT group: P=0.666, I2=0.0%; current HRT group: P=0.783, I2=0.0%). No publication bias was found among this subgroup .The studies included in the analysis of the risk of cortical cataract were the same as those in the analysis of nuclear cataract for each group. There was no significant difference for developing cortical cataract in past HRT group , current HRT group  and ever HRT group , as compared with non-HRT group. No substantial heterogeneity was detected among the included studies . ER has been detected in ocular tissues, including human lens epithelial cells . Davis ewith age . Secondlwith age ,46. TGF-with age .Several limitations of present meta-analysis should be considered. First of all, the postmenopausal hormone replacement therapy was estimated by the self-report questionnaires in most studies, resulting in misclassification of exposure status and a existing recall and selection bias, confounding the association of HRT use with risk of cataract. And the definitions of HRT use  were various in each study and contributed to an increase of heterogeneity. Secondly, the assessment of cataract or its subtypes varied between studies and a few studies even did not exhibit the case criteria and grading system. Thirdly, the adjusted factors in each study were different and some confounding factors which might account for the association of HRT with risk of cataract were not adjusted in some of the included studies. Although all studies were considered as high quality according to the corresponding quality assessment, the different study designs would inevitably lead to the increased inter-study heterogeneity. In addition, we did not try to contact the authors for original information which was not available in published form, and the estimates by statistical methodology might be a little different from the actual data. Because of the limited studies, the results should be interpreted with caution, and an update meta-analysis should be conducted with inclusion of newly published studies. Our study found that postmenopausal hormone use had a protective effect on cataract development. Further studies are needed to confirm these findings and make a better understanding of the biological mechanisms. Due to the reported effect of hormone replacement therapy on breast cancer, endometrial cancer, cardiovascular disease, osteoporosis and diseases of other systems, medical professionals should take all potential benefits and risks into account when considering HRT. Checklist S1PRISMA 2009 checklist in this meta-analysis.(DOC)Click here for additional data file.


CYP1A2) has been shown to influence the inducibility of CYP1A2 expression and thus might be associated with risk of several types of human cancer. However, the results of previous studies on the associations of this polymorphism with risk of cancer are not all consistent. To clarify the potential contribution of CYP1A2 rs762551 to cancer risk, we performed a meta-analysis of the published case–control studies.Genetic polymorphism (rs762551A>C) in gene encoding cytochrome P450 1A2  and 95% confidence interval (CI) were calculated using random effect model to evaluate the association of rs762551 with cancer risk. A Our analysis of 19 eligible case–control studies showed a significant association between rs762551C variant with risk of cancer in the genetic model of CC versus AA  and the dominant model . In subgroup analysis based on ethnicity, the rs762551CC genotype was associated with increased cancer risk (OR = 1.29, 95% CI = 1.27-1.63 in co-dominate model and OR = 1.17, 95% CI = 1.02-1.34 in dominant model in Caucasians, but not in Asians and the mixed population.CYP1A2 rs762551 polymorphism is likely to be associated with susceptibility to cancer in Caucasians.These results suggested that  The cytochromes P450 (CYPs) played an important role in the development of various cancers, since they involved in the metabolic transformation of numerous endogenous and exogenous compounds including carcinogens and anti-cancer drugs. CytochrCYP1A2 gene has been mapped on chromosome 15q24.1 and head to head shares a bidirectional promoter with CYP1A1 gene[CYP1A2 existed large inter-individual variability in the liver[CYP1A2 is regulated by constitutive expression and inducible expression from environmental chemicals[hemicals,6.CYP1A2 is highly polymorphic and there are more than 200 polymorphisms existed in CYP1A2 gene region according to NCBI dbSNP database (http://www.ncbi.nlm.nih.gov) and SNP500Cancer (http://variatgps.nci.nih.gov). Previous studies have extensively focused on CYP1A2 -164A>C polymorphism [CYP1A2. There also have several reported studied three common variations, that is -3860G>A polymorphism [CYP1A2 rs2069514 A allele has been demonstrated to associated with decreased enzyme activity in smokers and CYP1A2 rs762551 polymorphism is also associated with altered expression of CYP1A2 by cigarette smoking[s762551), which i2069514) and 15452069514),11. Thes smoking-14.CYP1A2 polymorphisms and the risk of various cancers, including lung cancer, breast cancer, colorectal cancer, stomach cancer and others in various populations[CYP1A2 variants in the development of all cancers involved.Recently, many studies have investigated the association of ulations-18. HoweCYP1A2 polymorphism with cancer risk in all ethnic populations. We evaluated the titles and abstracts of all relevant papers, but excluded case reports, editorials and reviews. All publications in English language with available full text matching the eligible criteria were retrieved. For inclusion in this meta-analysis, the identified articles had to provide information on the following: (1) using a case–control design, (2) sufficient data for examining an odds ratio (OR) with 95% confidence interval (CI) and (3) was a study of the CYP1A2 rs762551 polymorphism and cancer risk, (4) genotype distributions of polymorphism are consistent with hardy-Weinberg Equilibrium (HWE). In addition, we checked the references of relevant reviews and eligible articles that our search retrieved by two investigators independently.Remote PubMed, Embase, OVID, ScienceDirect, and Chinese National Knowledge Infrastructure database (between January 2003 and December 2011) was searched using the search terms: CYP1A2/P4501A2/phase II enzymes, polymorphism/polymorphisms/genotype and cancer/carcinoma/adenomas to identify all publications, which investigated the association of the CYP1A2 rs762551 A>C polymorphism and the risk of cancer by calculating pooled odds ratio (ORs) and 95% confidence intervals (CI) in genetic model of CC versus AA, dominant model (CC+CA versus AA) and recessive model (CC versus CA+AA). The significance of pooled OR was tested by Z test. The χ2-based Q-test was also used to examine the heterogeneity assumption[P≥0.05), a fixed-effects model could be used to calculate the combined OR. By contrast, if the P value of the Q tests is below 0.05, which showed that the study results statistically differ by heterogeneous case and sampling, a random-effects model could be more suitable. Since we used accumulating data from a series of studies, which had been conducted by researchers operating independently, the random model was more easily justified than the fixed model[We examined the association between sumption. If studed model,21. The The leave-one-out sensitivity analysis was conducted to determine whether our assumptions or decisions have a major effect on the results of the review by omitting each study (one at a time). FurtherCYP1A2 polymorphism, (2) no cancer case–control design, (3) review articles[CYP1A2 rs762551 polymorphism are shown in TableAfter preliminary screening as of 15 December 2011, there were 53 relevant publications fitting the key terms. We excluded 34 studies by (1) no related articles,26, (4) articles-30 and iarticles-18,31-41CYP1A2 rs762551 polymorphism were in agreement with the Hardy-Weinberg equilibrium in both cases and controls.The characteristics of populations and cancer types of final 19 publications were listed in TableCYP1A2 rs762551 polymorphism, the eligible studies involved in 8218 cases and 11165 controls. For each study, we investigated the association based on the assumption of different inheritance models of CYP1A2 rs762551 A>C polymorphism. In all inheritance models of rs762551 polymorphism, due to the between-study heterogeneity in the individual studies , the random-effect model was used to analyze the data[Regarding the data. We idenSeveral subgroup analyses were also performed according to the population ethnicity, cancer type, or source of control population Table. When weP for Q test and the I2 value also showed that none of single study affected the heterogeneity of this meta-analysis.In order to compare the sensitivity of the meta-analysis, we conducted a leave-one-out sensitivity analysis . The results showed the difference among these genetic models. We found the rs672551 polymorphism was associated with cancer risk under CC versus AA model and dominant model, but not under recessive model.For risk assessment, statistical uncertainty is associated with the model selected. In thist = 1.4870, P = 0.1553). However, the deficient funnel form of the funnel plot could be due to the relatively high heterogeneity with respect to the different ethnicity and the source of control population. Furthermore, the number of studies was relatively small and the publication bias may still exist.To evaluate the publication bias of rs762551 variant in the overall meta-analysis, the funnel plot and Egger’s test were used. In this analysis, the funnel plot showed a relatively symmetric distribution Figure, but theCYP1A2 rs762551 polymorphism and cancer risk, we conduced a meta-analysis involving in 8218 cancer cases and 11165 controls to indicate if the rs762551 polymorphism was significantly associated with risk of cancer. We evaluated the publication bias. The CYP1A2 rs762551 A>C genotypes funnel plot was approximately symmetrical and the Eggle’s test showed that there is no publication bias in the study of CYP1A2 rs762551 (P = 0.1553). We found that the carriers of CYP1A2 rs762551 C allele had a weak effect on the overall cancer risk in allele genetic model and in the dominant genetic model. These results suggested that the CYP1A2 rs762551 polymorphism might be useful for assessing cancer risk.Various studies provided evidences that genetics play an important role in determining cancer risk and association studies have been identified to evaluate cancer susceptibility. HoweverCYP1A2 gene is genetically polymorphic in human. To date, 177 SNPs have been deposited in the NCBI database and the frequency of these SNPs varies by ethnicity. Many of these SNPs are in linkage disequilibrium and a few SNPs have been reported to be functional[CYP1A2*1F (rs762551) polymorphism can result in 2–3 fold increase in activity/protein and has been associated with inducibility[CYP1A2 rs762551 polymorphism. However, we didn’t observe any correction of CC genotype with the cancer risk in subgroup analysis by cancer type. This biochemical mechanism was still unclear. In addition, due to the low OR in our study, our results should be interpreted cautiously. The CYP1A2 polymorphism may prove to be useful for assessing cancer risk.CYP1A2 is a critical enzyme involved in drug metabolism and carcinogen bioactivation. The expression and activity of CYP1A2 has been demonstrated to relate to the risk of various cancers,41,47. Cnctional,48. For cibility. Our curIt has been well known that cancer occurrence and mortality varied by ethnicity and geographic location. In thisAny meta-analysis has it limitations. To better interpreting the finding, several limitations need to be considered in current analysis. Firstly, potential publication biases may exist in this meta-analysis because studies excluded the non-English-language publications. Secondly, the total study size was still too small to perform subgroup analysis. Thirdly, this meta-analysis was based on unadjusted data due to a lack of detailed genotype information stratified by main confounding variables, such as gender, age, smoking status in original articles.CYP1A2 rs762551 polymorphism with cancer risk, mainly in Caucasian population. However, as a potentially powerful tool for assessing population effects of genetic variants, meta-analysis cannot replace for adequate genetic association studies. Also, to reach a more definitive conclusion, further gene-gene interaction and gene-environment interaction studies, which based on large sample size, are still needed in different population.In summary, our meta-analysis demonstrated a weak association of CYP1A2: Cytochrome P450 1A2; OR: Odd ratio; CI: Confidence interval; HAA: Heterocyclic aromatic amines, PAHs, polycyclic aromatic hydrocarbons; NNK: 4-methylnitrosamino-1- (3-pyridyl) -1-butanone; PCR-RFLP: Polymerase chain reaction-restriction fragment length polymorphism assay; SNPs: Single nucleotide polymorphisms.The authors declare that they have no competing interests.JY designed this study. HW and ZZ drafted the manuscript. HW, YL and SH contributed to the data extraction. ZZ and FF were responsible for data analysis. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/12/528/prepubTable S1. ORs (95% CI) of sensitivity analysis for rs762551.Click here for file


In the last four years, Genome-Wide Association Studies (GWAS) have identified sixteen low-penetrance polymorphisms on fourteen different loci associated with colorectal cancer (CRC). Due to the low risks conferred by known common variants, most of the 35% broad-sense heritability estimated by twin studies remains unexplained. Recently our group performed a case-control study for eight Single Nucleotide Polymorphisms (SNPs) in 4 CRC genes. The present investigation is a follow-up of that study. We have genotyped six SNPs that showed a positive association and carried out a meta-analysis based on eight additional studies comprising in total more than 8000 cases and 6000 controls. The estimated recessive odds ratio for one of the SNPs, rs3219489 (MUTYH Q338H), decreased from 1.52 in the original Swedish study, to 1.18 in the Swedish replication, and to 1.08 in the initial meta-analysis. Since the corresponding summary probability value was 0.06, we decided to retrieve additional information for this polymorphism. The incorporation of six further studies resulted in around 13000 cases and 13000 controls. The newly updated OR was 1.03. The results from the present large, multicenter study illustrate the possibility of decreasing effect sizes with increasing samples sizes. Phenotypic heterogeneity, differential environmental exposures, and population specific linkage disequilibrium patterns may explain the observed difference of genetic effects between Sweden and the other investigated cohorts. In recent years low-risk common alleles have attracted increasing attention in the search for the “missing heritability” in colorectal cancer (CRC). It concerns the part of heritability that cannot be explained by mutations in already known high-risk genes but should, according to twin studies, account for about 35% To date sixteen common variants have been identified through large multi-centre genome-wide association studies (GWAS) APC, MLH1, MSH6 and MUTYH) through a case-control association study in the Swedish population Against this background, a few years ago we attempted to assess the role of eight SNPs in four already known CRC genes  and approved by the Stockholm Regional Research Ethical Committee (Dnr 2002:489).APC D1822V), rs1799977:A>G (MLH1 I219V), rs1800932:A>G (MSH6 P92P), rs1800935:T>C (MSH6 D180D), rs3219484:G>A (MUTYH V22M) and rs3219489:G>C (MUTYH Q338H). MUTYH Q338H corresponds to Q324H in our first study MUTYH this corresponds to NM_001128425.1 and NP_001121897.1 for mRNA and protein, respectively Six SNPs in four different CRC genes were included in the analysis: rs459552:T>A (APC D1822V), was genotyped in seven studies, for a total of 8654 cases and 7731 controls. Four SNPs, rs1799977 (MLH1 I219V), rs1800932 (MSH6 P92P), rs1800935 (MSH6 D180D) and rs3219484 (MUTYH V22M) were genotyped in 8 studies for a total of 8308 cases and 7434 controls. The SNP with rs number 3219489 (MUTYH Q338H) was genotyped in 13 cohorts for a total of 12902 cases and 14602 controls.Details regarding the number of cases and controls in all fourteen studies are summarized in For all the subjects genomic DNA was extracted from peripheral blood by standard procedures. Additional information regarding localization of the tumor, age at diagnosis, gender and ethnicity was retrieved whenever possible. Out of 5770 controls with ethnicity information, 5647 were of Caucasian origin, the rest being mostly African American.http://www.kbioscience.co.uk/reagents/KASP_manual.pdf), which is a competitive allele-specific PCR SNP genotyping system that uses FRET quencher cassette oligos. Study 3 genotyped with the MassARRAY  technology. Study 4 genotyped by means of fluorescent hybridization probe melting curves using the Light Cycler instrument (Roche). Study 11 genotyped using Illumina HumanHap 550 Bead Arrays. Study 12 was genotyped by Sanger sequencing (cases only). Studies 13 and 14 were genotyped using Illumina HumanHap300 and Illumina HumanHap240S.In studies 1, 5, 6, 7, 8, 9 and 10 SNPs were genotyped using the TaqMan SNP Genotyping Assay . Genotyping in study 2 and 12 (controls only) was carried out by using the KASPar chemistry of the K-bioscience  (2 tests. Risks of CRC associated with genotypes were compared by odds ratios (ORs) with corresponding confidence intervals (CIs) based on logistic regression. Study heterogeneity was summarized using a Mantel–Haenszel test but we assumed that the studies were random samples from a general population and used a random effect model to summarize OR estimates under dominant, recessive and additive penetrance models in the meta-analyses. Results were represented by forest plots as follows: confidence intervals for each individual study were indicated by horizontal lines, single ORs by squares and summary estimates by diamonds with horizontal limits at confidence limits and width inversely proportional to the standard error. Meta-analyses were performed using the package rmeta in the free software environment for statistical computing R.Deviations of observed genotype frequencies in controls from those expected under Hardy-Weinberg equilibrium were assessed by χMSH6 P92P) under recessive and additive penetrance, with p-values equal to 0.04 and 0.03, respectively (The distribution of the genotypes in controls did not deviate from Hardy-Weinberg equilibrium in any study. Mantel-Haenszel tests identified study heterogeneity for rs1800932 (ectively . This doMUTYH Q338H), both under a recessive model  and assuming additive allelic effects . We ascribe the combined result mainly to the Swedish study, with individual ORs of 1.18  and 1.19   . The gooIn an attempt to validate the findings under recessive inheritance, we set up collaborations with additional groups and requested to genotype rs3219489 in their cohorts. In the end, additional 4234 cases and 6800 controls were included, adding up to a total of 12232 cases and 13380 controls .We updated the meta-analysis once more considering all samples regardless of tumor localization as well as stratifying them for colon and rectal tumors. As shown in APC D1822V), rs1799977 (MLH1 I219V), rs1800932 (MSH6 P92P), rs1800935 (MSH6 D180D) and rs3219484 (MUTYH V22M) samples were retrieved from eight additional studies totaling 8308 cases and 7434 controls. For the sixth SNP, rs3219489 (MUTYH Q338H), which was selected based on promising results from two samples of Swedish origin  gene, leading to genomic instability and abnormal and dis-regulated cell proliferation in the colonic epithelium MUTYH gene develop the MUTYH-associated polyposis (MAP) syndrome For all SNPs included in the analysis we were unable to confirm the associations with CRC risk found in the Swedish population. In particular, the recessive ORs of CRC for rs3219489 decreased from 1.52 in the original Swedish study to 1.18 in the Swedish replication cohort, to 1.08 (95% CI 1.00 to 1.17) in the first meta-analysis and to 1.03 (95% CI 0.97 to 1.10) in the updated meta-analysis . The sumTo date, 85 different MAP-associated mutations have been found The contrasting results on rs3219489 and its association with CRC risk in the Swedish versus other populations might suggest that the effect of this variant is specific for the Swedish population or not large enough in the other populations to be detected with the present sample size. For example, the statistical power of the updated meta-analysis was only 43% to detect a recessive OR of 1.10 . A closer look at the data actually shows that one of the German cohorts (ESTHER) gave results in agreement with our Swedish cohorts, with OR = 1.36 (95% CI 1.00 to 1.86) for colorectal cancer  and OR =On the other hand, in agreement with Swedish results, rs3219489 has also been shown to be associated with CRC risk in three independent studies in the Japanese population It is also possible that rs3219489 represents a risk-associated variant in the Swedish population in combination with environmental factors in the broad sense. For example, screening programs for CRC in Sweden could result in a diagnosis earlier in life, thus inflating the ORs estimated in Sweden. Another alternative is that the polymorphism is in linkage disequilibrium with other unidentified causal variants. The marker and the causal variant could be located on the same risk haplotype in the Swedish population and on different haplotypes in other populations.Independently of the unknown reason for replication failure, the results from the present study clearly illustrate the possibility of decreasing effect sizes with increasing collections of individuals, a phenomenon well-known in the field of genetic epidemiology denominated the winner's curse Table S1Number of cases and controls genotyped in the fourteen studies.(DOC)Click here for additional data file.Table S2Genotype counts and allele frequencies for rs459552 (APC D1822V), rs1799977 (MLH I219V), rs1800932 (MSH6 P92P), rs1800935 (MSH6 D180D), rs3219484 (MUTYH V22M) and rs3219489 (MUTYH Q338H). The estimated odds ratios with 95% confidence intervals for individual studies are also shown, together with combined ORs, 95% CIs and probability values for OR = 1 based on random effects model and probability values for study homogeneity under dominant, additive and recessive penetrance.(DOC)Click here for additional data file.Table S3Genotype counts and allele frequencies for rs3219489 (MUTYH Q338H).(DOC)Click here for additional data file.Table S4Genotype counts for colon and rectal cancer cases in studies with available information on tumor location.(DOC)Click here for additional data file.