CYP2A6*2, CYP2A6*3, CYP2D6*3, CYP2C19*3, and CYP3A4*17 variant alleles are virtually absent in Chileans. CYP1A1*2A allele frequency (0.37) is similar to that of Caucasians and higher than that reported for Japanese people. Allele frequencies for CYP3A5*3(0.76) and CYP2C9*3(0.04) are similar to those observed in Japanese people. CYP1A1*2C(0.32), CYP1A2*1F(0.77), CYP3A4*1B(0.06), CYP2D6*2(0.41), and MTHFR T(0.52) allele frequencies are higher than the observed either in Caucasian or in Japanese populations. Conversely, CYP2C19*2 allelic frequency (0.12), and genotype frequencies for GSTT1 null (0.11) and GSTM1 null (0.36) are lower than those observed in both populations. Finally, allele frequencies for CYP2A6*4(0.04), CYP2C8*3(0.06), CYP2C9*2(0.06), CYP2D6*4(0.12), CYP2E1*5B(0.14), CYP2E1*6(0.19), and UGT2B7*2(0.40) are intermediate in relation to those described in Caucasian and in Japanese populations, as expected according to the ethnic origin of the Chilean population. In conclusion, our findings support the idea that ethnic variability must be considered in the pharmacogenomic assessment of cancer pharmacotherapy, especially in mixed populations and for drugs with a narrow safety range.Cancer is a leading cause of death worldwide. The cancer incidence rate in Chile is 133.7/100,000 inhabitants and it is the second cause of death, after cardiovascular diseases. Most of the antineoplastic drugs are metabolized to be detoxified, and some of them to be activated. Genetic polymorphisms of drug-metabolizing enzymes can induce deep changes in enzyme activity, leading to individual variability in drug efficacy and/or toxicity. The present research describes the presence of genetic polymorphisms in the Chilean population, which might be useful in public health programs for personalized treatment of cancer, and compares these frequencies with those reported for Asian and Caucasian populations, as a contribution to the evaluation of ethnic differences in the response to chemotherapy. We analyzed 23 polymorphisms in a group of 253 unrelated Chilean volunteers from the general population. The results showed that  Cancer is a leading cause of death worldwide and the total number of cases globally is increasing. The number of cancer deaths is projected to increase 45% from 2007 to 2030 (from 7.9 million to 11.5 million deaths), influenced in part by an increasing and aging global population. The estimated rise takes into account expected slight declines in death rates for some cancers in high resource countries. New cases of cancer in the same period are estimated to increase from 11.3 million in 2007 to 15.5 million in 2030 WHO, . In ChilThough the principal achievements in the fight against cancer has been those related to preventive measures, the success in the treatment of an established cancer depends on the cancer stage when detected, on the type of cancer, and on its location. It is quite infrequent to find patients considered as “therapeutical success” because there is always a possibility that a tumor process may appear back  system is the most important metabolic system responsible for the oxidation of numerous chemotherapeutic agents, and it is responsible to a great extent for the variability observed in response to drugs. For example, some enzymes of the CYP3A family play an important role in the metabolism of epidophilotoxin, ifosfamide, tamoxifen, taxol, and vinca alkaloids. Cytochrome P450 enzymes are also of great importance in the study of chemotherapy resistance. , are polymorphic isoenzymes which show a wide subcellular distribution. GST alpha (α), kappa (κ), mu (μ), pi (π), omega (ω), sigma (σ), theta (θ), and zeta  which converts 5,10-methylene tetrahydrofolate to 5-methyl tetrahydrofolate. This reaction is required for the multistep process that converts the amino acid homocysteine to another amino acid, methionine. Polymorphisms of this enzyme predispose to serious bone marrow toxicity during treatment with agents that inhibit folate synthesis . The study group has a 37% Amerindian-Caucasian admixture, as determined by ABO blood group distribution  and DNA samples were stored at -20°C until further analysis.Extraction of genomic DNA was done by a standard procedure from whole blood using a commercial kit  or polyacrylamide gel (16%) according to methods previously reported .Genomic DNAs from peripheral blood were amplified by PCR using specific primers for detection of the specific allelic variants in study. For detection of polymorphisms Pharmacogenetic research is directed to identify genes or gene products associated with diseases and, especially, allelic variants in enzymes of biotransformation that alter the individual response to drugs. These variants can modify the magnitude of the pharmacological effect, the threshold of toxicity, the efficacy of the drug, side effects, and drug–drug interactions. In this respect, it is particularly important at the time, to define pharmacogenetic profiles of patients with cancer to determine suitable dosages, to improve efficacy, to avoid adverse reactions of the traditionally used drugs, and to develop new drugs according to the genetic – metabolic profile of the patients  CYP2D6 known were genotyped. We select only CYP2D6 polymorphisms that have shown better reported relationship with plasma levels of antineoplastic drugs and those that have higher allele frequencies, based on a previous pilot study in Chilean subjects . Similarly, same criteria were used for choosing the other studied polymorphisms, based on both literature and our own previous research. Nevertheless, some potentially relevant CYP variants are currently under investigation in our laboratory , to complement the results shown in this paper.S-methyltransferase (TPMT), a cytosolic phase II enzyme involved in the metabolism of azathioprine, thiopurine, and thioguanine  there is very good and complete information about these polymorphisms in Japanese people and (b) recently, have been reported no great differences among Japanese and other Asian populations, particularly with respect to Chinese population . In this sense, our results agree with these observations when we compare the analyzed sub-group with Asian and Caucasian populations Table .As Chilean population represents a mixed ethnicity mainly between native-Americans and Caucasians (mostly Spaniards) the data obtained might help to understand inter ethnic differences not only for single polymorphisms, but also the function of simultaneous polymorphisms in metabolic genes in each subject, to explain differences in response to chemotherapy.CYP1A1, CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, GSTM1, GSTT1, UGT2B7, and MTHFR) in Chilean people, which can give course for a genetic – population investigation of these polymorphisms helping to the understanding of susceptibility to drugs and pathologies in this population, which already has been suggested by our group of research for some specific genes (Quiñones et al., This investigation contributes to have a first pattern of several relevant polymorphisms in metabolizing enzymes (The knowledge of genetic variants involved in the metabolism of the antineoplastic drugs in the Chilean population will help to the prediction of their clinical efficacy and/or toxicity, and therefore, will help us to the design personalized cancer treatments to improve therapeutic response and diminish the adverse effects improving cost-efficacy of treatments.Finally, based on scientific literature and our experience, we believe that, at least in Chilean population, MTHFR/methotrexate, GST/cisplatin, and CYP2D6/tamoxifen are the potential more relevant gene/drug pairs which are closer for monitoring use in clinical practice.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


ADIPOQ gene are associated with metabolic syndrome in Chinese Han populations. However, data is still conflicting. The objective of this study was to examine the associations of the adiponectin genetic variants with metabolic syndrome by a case-control study and meta-analyses in Chinese.The prevalence of metabolic syndrome has been rising worldwide, including in China, but knowledge on specific genetic determinants of metabolic syndrome is very limited. A number of studies have reported that polymorphisms in the ADIPOQ rs2241766 (+45T>G in exon 2), rs266729 (−11377C>G in promoter) and rs1501299 (+276G>T in intron 2) polymorphisms with metabolic syndrome in a Hubei Han Chinese population with 322 metabolic syndrome patients and 161 normal controls recruited from the Yichang, Hubei. Then we comprehensively reviewed the association between ADIPOQ rs2241766/rs266729/rs1501299 and metabolic syndrome in the Chinese populations via a meta-analysis. The strength of association was assessed by odds ratios (ORs) with 95% confidence intervals (CI).We first investigated the association of P = 0.033). The logistic regression analysis adjusted by gender and age showed a nominally significant association for rs2241766 GG+GT genotype  and rs1501299 GG genotype in recessive model . However, no association was observed for rs266729 in our sample. We identified thirteen studies for rs2241766 , three studies for rs266729, and eleven studies for rs1501299  in Chinese. Meta-analysis indicated significant associations for the rs2241766 G allele , rs266729 GG+GT genotypes  and rs1501299 GG+TG genotypes .The G allele frequency of rs2241766 in metabolic syndrome patients was significantly higher than those of controls group (29.8% vs 23.3%, OR = 1.40, ADIPOQ as a pleiotropic locus for metabolic syndrome and its components in the Han Chinese population.Our results demonstrated  Metabolic syndrome (MetS) refers to a cluster of multiple metabolic abnormalities,including abdominal obesity, dyslipidemia ), hypertension, insulin resistant (IR), impaired glucose tolerance (IGT), and elevated fasting glucose The familial nature of MetS, the marked difference in the prevalence among various racial groups, and differences in concordance rates between monozygotic twins clearly suggested that MetS is under genetic control. Heritability estimates for MetS range from 10% to 42% CETP and LPL are associated with MetS in Indian Asian male population APOA1/C3/A4/A5 gene cluster region (SNP rs964184) was associated with MetS in recent GWAS of 4 Finnish cohorts consisting of 2637 MetS cases and 7927 controls (both free of diabetes)  The evidence of genetic determinants fueled the study to identify susceptibility genes for MetS using linkage or association studies. Genome-wide linkage studies in multiple populations found evidence for linkage of MetS on chromosome 1, 2, 3q37, 7q, 16 ADIPOQ) gene is located on human 3q27, a susceptibility locus for MetS and its components. ADIPOQ expresses adipocyte-specific secretory protein. The data from human studies suggested that plasma ADIPOQ level is related to each component of MetS. It is well documented that lower plasma ADIPOQ levels were associated with obesity ADIPOQ levels ADIPOQ concentration.Adiponectin (ADIPOQ SNPs in the Chinese population was shown in ADIPOQ gene have been reported to be associated with MetS in Chinese populations Linkage disequilibrium (LD) pattern of ADIPOQ rs2241766, rs1501299, rs266729 polymorphisms and MetS in a Hubei Han Chinese population, and to systematically review the association of ADIPOQ rs2241766/rs266729/rs1501299 with MetS in Chinese via a meta-analysis.In the present study, we aimed to investigate the association between All participants gave written informed consent. The protocol was in accordance with the Helsinki Declaration, and was approved by the Institutional Review Boards of the Yiling Hospital in Yichang, Hubei Province. The present study included a total of 483 individuals of Hubei Han Chinese, comprising 322 MetS patients  and 161 controls . The IDF definition of MetS 2 (m2) and waist (cm)/hip (cm). Clinical parameters measured included FPG, 2 hours' postprandial blood glucose (PBG), SBP and DBP, total cholesterol, TG, HDL-cholesterol, LDL-cholesterol, and fasting insulin.The weight, height, waist and hip circumference were measured in all individuals. BMI and waist to hip ratio (WHR) were separately calculated as weight (kg)/heightADIPOQ gene were selected to genotype using polymerase chain reaction – restriction fragment length polymorphism (PCR-RFLP) method. The primer sequences and the annealing temperature of the PCR were shown in 2+ Plus), 0.5 μl dNTP mixture. The PCR amplification conditions were as follows: an initial denaturing cycle at 94°C for 5 min, followed by 35 amplification cycles , and a final extension at 72°C for 5 min.Genomic DNA was obtained from whole blood leukocytes using standard phenol/chloroform method. Three SNPs  in the 2 test before association analysis. The genotypic and allelic frequencies between MetS patients and controls were compared using χ 2 test. The genotype – disease association analyses were performed by logistic regression analysis. A P value less than 0.05 was considered statistically significant. Statistical analyses were performed using SPSS for Windows software (version 11.5). Statistical power was estimated by the ‘Case – control for discrete traits’ module of the web-based Genetic Power Calculator (http://pngu.mgh.harvard.edu/~purcell/gpc/qcc.html), which takes the control-case ratio of the study sample into account.The genotype distribution in the cases and controls were separately tested for Hardy – Weinberg equilibrium using the χ ADIPOQ” or “adiponectin gene polymorphism”, “AMP1”, and “metabolic syndrome” or “MetS” or “metabolic syndrome X” or “ syndrome X” as key words. The references of all computer-identified publications were searched for additional studies. The PubMed option “Related Articles” was used to search for potentially relevant papers. Reference lists in retrieved articles were also screened. Without any language restriction, we only selected published manuscripts . Studies included in the meta-analysis must meet all the following criteria: (1) assessed the associations of polymorphisms in the ADIPOQ gene with MetS; (2) used case – control or cohort design; (3) provided odds ratio (OR) with 95 % confidence interval (CI), or genotype frequency among case and control group; (4) for duplicate publications from the same patient population, only the paper that had the largest population, contained more useful information or the latest one was selected. The following information was extracted: first author name, year of publication, ethnicity, sample size, genotype distribution and minor allele frequency in cases and controls, p value for allele frequency  and VIP Information were searched up to August 2012, using “adiponectin” or “requency .ADIPOQ polymorphisms with MetS.We found forty-six published potentially relevant papers but only fourteen meet selection criteria. Among the forty-six papers, twenty-six were excluded due to irrelevance. In addition, four articles were excluded because they studied other polymorphisms or duplicate publications. Two studies from Korea and Croatia were also excluded. Moreover, one paper included two studies. From the above, 13 Chinese studies with a total of 2,684 cases and 2,864 controls were included in rs2241766 analysis, 11 Chinese studies with a total of 2,889 cases and 3,304 controls were included in rs1501299 analysis, 3 Chinese studies including our independent study with a total of 1,486 cases and 1,379 controls were included in rs266729 analysis. ADIPOQ gene with MetS were estimated by calculating pooled OR and 95% CI under additive, dominant and recessive genetic models by using stata 10.0 software. ORs were calculated using 2×2 contingency tables for each study. The χ 2-based Q-test and the inconsistency index (2I) were applied to assess heterogeneity among studies. Sensitivity analysis was conducted by removing one study at a time and calculating the pooled ORs for the remaining studies. The Z-test was used to calculate the P value of the overall effect for the meta-analysis. Pooled ORs were computed by the fixed-effects method of Mantel-Haenszel (peto method) for data combined under no heterogeneity between studies (P>0.1). If significant heterogeneity exists between studies (P≤0.1), then a random effects model of Der-Simonian-Laird (D-L method) is appropriate for data combined. The conservative Egger's regression analysis was used to evaluate publication bias.The associations of polymorphisms in the t-test analysis showed that the gender, age, height, weight, waist circumference, hip circumference, SBP, DBP, FPG, BMI, triacylglycerol, HDL-cholesterol, and LDL-cholesterol, in MetS were significantly higher than those of the controls group. Since height, weight, waist circumference, hip circumference, SBP, DBP, FPG, BMI, triacylglycerol, HDL-cholesterol, and LDL-cholesterol were components of MetS, only gender and age were used as covariates to be adjusted in association analyses.Clinical characteristics of the study subjects are shown in P>0.05). The G allele and GG+TG genotype frequencies of rs2241766 in MetS patients were significantly higher than those of controls group . The logistic regression analysis adjusted by gender and age showed a nominally significant association for rs2241766 GG+GT genotype .The genotypic distributions of the rs2241766 polymorphism was in Hardy-Weinberg equilibrium in both MetS patients and controls group  for the rs2241766 G allele, 1.19  for the GG+GT genotypes in dominant model (P = 0.005) for the G allele, OR = 1.17 for GG+GT genotypes  in dominate model.We identified thirteen Chinese studies for the nt model . We furtP = 0.015) for the G allele, 0.80  for GG+GT genotypes in dominant model.No association was observed for either rs266729 G allele, GG genotype in recessive model or GG+CG genotypes in dominant model with or without adjustment for gender and age in our sample. Because only three association studies of the rs266729 polymorphism with MetS were found in Chinese, we pooled genotype data of all three studies. The allele frequencies for G were 0.249 in the MetS group, and 0.278 in the control group. The pooled OR was 0.862  and the GG genotype in recessive model without  or with adjustment of gender and age  in our sample.An association trend was observed for rs1501299 G allele , the GG+TG genotypes in dominant model  and for GG vs TT in additive model  (P<0.001) .P (0.014–0.001) value and heterogeneity (I2 = 2.3∼26.9%) for rs2241766. However, the result of meta-analysis for rs1501299 was not stable. The meta-analysis result of the allele model becomes significant after removing Yang's P = 0.009, OR = 1.33, 95%CI = 1.08–1.66) or Chen's P = 0.014, OR = 1.33, 95%CI = 1.06–1.67) studies that showed an association trend in the opposite direction.A sensitivity analysis was conducted by removing one study at a time and calculating the pooled ORs for the remaining studies. The results indicated that none of the individual studies influenced the pooled ORs , P<0.001, I2 = 84.8%). Meta-regression analysis including covariates the age in case groups and control groups, publication date, sample size, diagnostic criteria, region and gender, showed that only the age in case groups and control groups significantly contributed to the heterogeneity . The inconsistency index I2 decreases from 84.8% to 60.3% after removing Huang's study A significant heterogeneity was observed for rs1501299 in allele analysis . The association was further confirmed by our meta-analysis, which involved 2,684 case patients and 2,864 control in Chinese populations. A weak association was found for the rs1501299 GG genotype in recessive model in our sample, and significant associations were found for the G allele , the GG+TG genotypes in dominant model  and for GG vs TT in additive model  in meta-analysis. The result from pooled three genotype data suggested that rs266729 was significantly associated with MetS in additive  and dominant models . Therefore, both our study in Hubei Han Chinese and meta-analyses in the Chinese population suggested that polymorphisms in the ADIPOQ gene were associated with MetS risk.In the present study we examined the association of rs2241766, rs1501299 and rs266729 polymorphisms in the ADIPOQ gene and MetS in the Chinese populations. Thirteen small studies previously conducted in Chinese populations examined the rs2241766 polymorphism in relation to MetS with inconsistent results. Only two studies P = 0.015). These results highlight the pivotal role of systematic review to draw firm conclusions.To our knowledge, this study represents the first meta-analysis between polymorphisms in the ADIPOQ gene and plasma ADIPOQ levels P = 0.01) and rs1501299 G>T (P = 0.01), whereas variant alleles at SNP rs266729 C>G (P = 0.0003) were associated with a lower ADIPOQ level. Patients with rs266729CG, CG+GG genotypes  had higher levels of serum ADIPOQ than those with the CC genotypes in a Chinese Han population ADIPOQ played a role in modulating ADIPOQ secretion. Therefore, polymorphisms in the ADIPOQ gene may regulate the serum ADIPOQ levels, thereby influence the risk of MetS.The low serum ADIPOQ level is a strong risk factor for MetS ADIPOQ gene and T2DM have been published ADIPOQ gene and blood pressure and essential hypertension in Chinese populations ADIPOQ rs1501299 T  was associated with an increased risk of obesity in a recent meta-analysis ADIPOQ as a pleiotropic locus for MetS and its components, presumably serving as an important physiological and pharmacological target in the prevention and treatment of MetS.Six meta-analysis of the association between the genetic variants in the Although we limit our meta-analysis to the Chinese population, meta-analysis still revealed significant between-study heterogeneity for SNP rs1501299 . The souWe acknowledged that there were some limitations in our study. First, sample size in our study was comparatively small and had insufficient statistical power to detect the association. Assuming the prevalence of 30%, and the minor allele frequencies of the marker and QTL are both 0.2, a marker is in complete LD (D' = 1) with a QTL, and using a dominant genetic model, this study had about 68% power at a significance level of α = 0.05 to detect an effect size of 1.4. Second, the present meta-analysis was based primarily on unadjusted effect estimates and the confounding factors were not controlled for. Third, due to lack of original data, the effects of gene – gene and gene-environment interactions were not considered in our current study. In addition, a weak publication bias was detected for the rs2241766 dominant model.ADIPOQ is a pleiotropic locus for MetS and its components in Chinese Han population. In the future, well-designed studies with large sample sizes in diverse ethnic populations are warranted.In conclusion, our results and meta-analysis demonstrates that


To investigate the association between rs1820453 which located in the promoter region of yes-associated protein 1 (YAP1) gene and breast cancer (BC) risk.YAP1 gene expression. The association between rs1820453 and BC risk was significantly identified with the odds ratio (OR) was 1.27  =1.03-1.57) under allelic model when adjusted by age and menopausal status. In addition, the correlation analysis of rs1820453 and YAP1 expression level found that this variant was significantly associated with the gene expression in Chinese population. When compared with level of mRNA expression of the AA genotype (6.011±0.046), the mRNA expression level in CC genotype (5.903±0.026) was statistically lower (P=0.024).We conducted a hospital-based case-control study including a total of 480 BC cases and 545 cancer-free controls in Chinese population. Then the expression quantitative trait locus (e-QTL) analysis was performed to explore the possible function of rs1820453 to the The results from this study suggested that rs1820453 A>C change may affect the gene expression and contribute to the risk of developing BC in Chinese population though larger sample-size studies along with functional experiments were anticipated to warrant the results. BRCA1 and BRCA2 account for about 15% of the familial aggregation of BC [Breast Cancer (BC) as the most commonly diagnosed cancer among female in the world has been one of the most important global public health problem with much attention has been paid on it . Much efon of BC .YAP1) located at 11q22, a site of frequent loss of heterozygosity in sporadic BC [YAP1 gene encoded was a transcriptional coactivator which was important in P73-dependent apoptosis [Yes-associated protein 1 gene . Genomic DNA was extracted from the whole blood sample of all participants using the RelaxGene Blood System DP319-02  according to the manufacturer’s directions. The quantity and quality of DNA　was assessed by the NanoDrop 2000 spectrophotometer. The genotype of rs1820453 was determined by the TaqMan SNP Genotyping Assay  using the 7900HT Fast Real-Time PCR System . To ensure quality control, 5% duplicated samples were randomly selected to evaluate the reproducibility and with 100% concordance. Moreover, genotyping was performed without knowledge of case or control status. The call rate of genotyping was 98.3 %, and 480 patients and 545 controls were finally included for subsequent statistical analyses. 2 test for genotypes in the control group. Difference in distribution of demographic characteristics between cases and controls were evaluated by χ2 test and t test where appropriate. The association between BC risk and rs1820453 was assessed by the odds ratio (OR) along with 95 % confidence interval (95 % CI) using unconditional multivariate logistic regression analysis with adjustment for age and menopausal status. All statistical analyses were performed using the SPSS 12.0 software with two-sided P value less than 0.05 was considered to be statistical significance. Hardy-Weinberg equilibrium (HWE) for rs1820453 was evaluated by goodness-of-fit χhttp://app3.titan.uio.no/biotools/help.php?app=snpexp) [The genotype-phenotype analysis was carried out to explore the possible function of rs1820453 using the SNPexp database which was available online (=snpexp)  after siP= 0.417) were identified. In addition, there were more postmenopausal persons in controls but no significant distribution difference (P= 0.094) of menopausal status between cases and controls was found. The distributions of demographic characteristics of the participants were presented in P= 0.942). When considered the A allele as reference, the C allele was significantly associated with increased BC risk with the OR=1.27 (95 % CI=1.03-1.57) after adjusted by age and menopausal status under logistical regression analyses. The persons who carried the CC genotype had significantly increased BC risk when compared to those who carried AA genotype . Moreover, the significant association between rs1820453 and BC risk were also identified in recessive and additive models with the OR of 1.98 (95 % CI=1.16-3.38) and 1.26 (95 % CI=1.03-1.54), respectively. When classified BC cases according to the Estrogen Receptor (ER) and Progesterone Receptor (PR) status, significant association of BC risk and rs1820453 was only remained in ER-PR- specified BC subgroup but not in ER+/PR+ subgroup .The genotypes distribution of rs1820453 for cases and controls and the association between this variant and BC risk were summarized in YAP1 mRNA expression in 44 (1 missing) unrelated Chinese Han population found that when compared with the levels of mRNA expression in 26 cell lines with rs1820453 AA genotype (6.011±0.046), 2 cell lines with the CC genotype had statistically lower levels of mRNA expression   . Howeverectively . The allP= 0.023). Then the genotype-phenotype correlation analysis of rs1820453 and YAP1 gene mRNA expression level found that the mRNA expression level was significant lower in cell lines with CC genotype than the cell lines with the AA genotype in Chinese population (P= 0.024). But it was worth noting that the association of rs1820453 A>C change and YAP1 gene mRNA expression was not significantly identified in the all four populations (P for additive model= 0.858). All of these suggested that rs1820453 may be the risk factor for BC through influencing the activity of YAP1 gene in Chinese but not in other populations. Certainly, more population-based studies in other ethnic populations are anticipated to further explore the association of rs1820453 and BC risk. In the present case-control study consisted of 480 cases and 545 controls, we identified that rs1820453 A>C change significantly associated with increased BC risk in Chinese population with the OR of 1.27 under the allelic model (YAP1 gene as a transcriptional coactivator played an important role in the P73-driven apoptosis pathway. It has been reported that the function of P73 was critical for cellular responding to the cytotoxic chemotherapy and the P73 level in tumor cells reduced by siRNA or genetic mutations may lead to strong reduction of apoptosis induced by DNA damage [YAP1 gene which may result in the change of YAP1 activity may finally impact the DNA-damage induced apoptosis pathway. The protein YAP1 encoded by A damage ,20. On tYAP1 gene and the variant A>C change may cause down regulation of YAP1 which in turn might weaken the P73-dependent apoptosis of cancer cells and suppress the chemotherapy-induced cancer cell death. All of which then resulted in faster cancer progression. The gene report experiment from Wu C et al, found that rs1820453 A>C change may affect YAP1 promoter activity; and the rs1820453 A-containing promoter had higher transcriptional activity. The cells containing rs1820453 A allele drove a significantly higher gene expression when compared to the cells containing rs1820453 C allele [The rs1820453 located in the promoter region of In addition to the interaction with P73-driven tumor suppression pathway, present study had found that YAP1 displayed as a protein that integrate another RASSF1A-driven tumor suppressor pathway with the P73 pathway . Though we first identified that rs1820453 was significantly associated with increased BC risk in the current study; some limitations also should be acknowledged. First, this was a hospital-based case-control study which may bring in selection bias during the participants recruitment. Moreover, the sample size of this study was relatively small. Therefore, it would be important to confirm the results in larger and prospective studies. In addition, environmental risk factors were also important in the developing of BC. However, we did not analysis the environmental effect or the gene-environment interaction effect due to the lacking of information on exposure of environmental risk factors. And the estimated effect of rs1820453 on BC risk was not adjusted by some confounding characteristics such as age of menarche and family history owing to the uncompleted collection of the relevant information. Furthermore, though the e-QTL analysis used the HapMap data identified significant association between the mRNA expression level of YAP1 and rs1820453 genotypes, the sample size was relatively small, especially the CC genotypes in Chinese was just 2. Meanwhile, we did not perform more functional experiments to further support the results because of the deficiency of samples.In conclusion, our case-control study and e-QTL analysis identified rs1820453 was associated with BC risk. The results provided a basic insight of this variant contribute to the susceptibility of BC though functional analyses and larger sample size studies were needed to warrant the results.


ITPKC (rs28493229) is responsible for susceptibility to KD. We collected DNA samples from 1,531 Taiwanese subjects  for genotyping ITPKC. In this study, no significant association was noted for the ITPKC polymorphism (rs28493229) between the controls and KD patients, although the CC genotype was overrepresented. We further combined our data with previously published case/control KD studies in the Taiwanese population and performed a meta-analysis. A significant association between rs28493229 and KD was found . Importantly, a significant association was obtained between rs28493229 and KD patients with aneurysm formation . Taken together, our results indicated that C-allele of ITPKC SNP rs28493229 is associated with the susceptibility and aneurysm formation in KD patients in a Taiwanese population.Kawasaki disease (KD) is characterized by systemic vasculitis with unknown etiology. Previous studies from Japan indicated that a gene polymorphism of  Kawasaki disease (KD) is a multi-systemic vasculitis with unknown etiology which was first reported by Kawasaki et al. While these clinical features of KD are recognized, their underlying immunopathogenic mechanisms are still unclear; in particular, the culprit for developing CAL in patients with KD remains as yet to be uncovered. KD is regarded as an immune disorder of host rather than an infectious disease. From our previous reports, monocytosis and T helper 2 (Th2) immune response were associated with CAL formation ITPKC gene associated with KD susceptibility and the development of coronary artery lesions ITPKC (rs28493229) located in intron 1 that resulted in the different transcriptional level of mature mRNA by interfering the RNA splicing efficiency. ITPKC is a kinase that phosphorylates inositol 1,4,5-trisphosphate (IP3). IP3 is an important factor in the initiating of calcium release from endoplasmic reticulum Genetic association of KD with inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) in a genome wide scan has been recently reported by Onouchi et al. They first indicated a functional SNP in the 3-mediated calcium signaling pathways can activate the translocation of nuclear factor of activated T-cells (NFAT) that further evoked the release of cytokines and the initiation of immune responses 2+/NFAT signaling pathways. High level expression of ITPKC can attenuate the Ca2+/NFAT pathways via over phosphorylation of IP3 that resulted in reduction of T cell activation and IL-2 production. ITPKC (rs28493229) was confirmed to associate with the susceptibility of Kawasaki disease and CAL formation. However, the replication studies of ITPKC (rs28493229) from Taiwanese populations were controversial The empty of endoplasmic further evokes store-operated calcium influx. Store-operated calcium influx has been shown to involve in the activation of T cells. For example, IPITPKC (rs28493229) and the risk of KD using a case-control study. The relationship of clinical data including CAL, intravenous immunoglobulin (IVIG) treatment response, and aneurysm formation with genetic polymorphisms of ITPKC were also evaluated.In this study, we examined the association between the All subjects studied were children with the diagnosis of KD and were admitted at Chang Gung Memorial Hospital at Kaohsiung between 2001 and 2009. All patients were treated with a single infusion of IVIG (2 g/kg) administered over a 12-hour period. Aspirin (3–5 mg/kg/day) was administered until all signs of inflammation were resolved or regression of CAL was detected under two-dimensional (2D) echocardiography; these conditions were the same as that in our previous studies Blood cells were subjected to DNA extraction by treating them first with 0.5% SDS lysis buffer and then protease K (1 mg/ml) for digestion of nuclear protein for 4 h at 60°C. Total DNA was harvested by using the Gentra extraction kit followed by 70% alcohol precipitation.Genomic DNA was extracted from whole blood samples by using the standard method. Genotyping was carried out using the TaqMan Allelic Discrimination Assay . Briefly, the polymerase chain reaction (PCR) was performed by using a 96-well microplate with the ABI 9700 Thermal Cycler. The thermal cycle conditions were as follows: denaturing at 95°C for 10 min, followed by 40 cycles of denaturing at 92°C for 15 s and annealing and extension at 60°C for 1 min. After PCR, fluorescence was measured and analyzed using the System SDS software version 1.2.3. Average genotyping successful rate in our lab is around 95.7%, so some individuals are without genotype data.2-test or the Fisher exact test. The statistical differences in the genotype and allele frequency of KD patients with and those without CAL formation and patients responding to IVIG and those showing resistance were assessed using the χ2-test. For the meta-analysis, sufficient data were available from other two KD association studies, and the odds ratios with 95% confidence intervals were calculated for the risk factors investigated. Combined odds ratios were calculated using Mantel–Haenszel method with a fixed effect model for each outcome measure. Statistical analysis was completed using the rmeta package of R software.SAS 9.1 for Windows was used for analysis. The statistical differences between cases and controls in genotype and allele frequency were assessed by the χITPKC SNP genotypes was in accordance with the Hardy-Weinberg equilibrium for both cases and controls  in the Taiwanese population  had CAL formation and 43 patients (12.6%) were resistant to initial IVIG treatment . We furITPKC in the pathogenesis of CAL in KD patients. A subset analysis where cases reported having aneurysm formation was performed. In this study, 14 patients (4.1%) had aneurysm formation  (ITPKC was associated with the KD patients with aneurysm formation. KD patients carry rs28493229 homozygous C/C genotype had a 24.5-fold (P = 0.001) increased risk of aneurysm formation when compared with those with C/G and G/G genotypes.We further identify the role of SNP rs28493229 of owed up) . As showITPKC (rs28493229) that reduced the expression of ITPKC associated with KD susceptibility and formation of coronary artery lesions from Japan and US cohort. Not only did it indicated that genetic factors contributed to the susceptibility as well as the pathogenesis of KD, but this was the first unequivocal identification of the functional SNP in a new gene (ITPKC). However, the replication studies of ITPKC (rs28493229) from Taiwanese populations were with controversial results. Chi et al. ITPKC SNP rs28493229 and KD susceptibility or CALs in Taiwanese children. Interestingly, reports from Lin et al. ITPKC SNP rs28493229 is associated with KD susceptibility and BCG scar reactivation during the acute phase but not associated with the develop or severity of CAL formation. As shown in ITPKC rs28493229 is a risk allele in the KD susceptibility in the Taiwanese population. In this study, we also first analysis the association between rs28493229 with IVIG treatment response and aneurysm formation. Our results indicated that C allele of ITPKC rs28493229 had significant higher risk to have aneurysm formation. Although the exact role of ITPKC in the development of KD is unclear, it may function as the negative regulator in the regulation of immune genes or to be involved in the T cell activation mechanisms. The results also, at least, reflect the facts that complex genetic, ethnic, and environmental factors are involved in the association with KD ITPKC genetic association studies in the Taiwanese population, we attribute this to the population migration between Taiwan and China, Thailand, Indonesia, Malaysia, Vienna and other Asia areas, due to the increase of genetic diversity between cities in the south or north of Taiwan.Kawasaki disease is an acute vasculitis that may lead to acquired coronary artery aneurysms. Many genetic factors have been reported to involve in the development of coronary artery aneurysms. A major advance came when Onouchi et al. performed a large scale of genome wide screening to study the polymorphisms in KD patients 3 via phosphorylation steps. Two possible signaling pathways that may involve in the increase of intracellular calcium concentration can be triggered by IP3. First, upon binding to the IP3 receptor (IP3R) on the endoplasmid reticulum, IP3 triggers the release of intracellular calcium from stores. Second, store empty resulted in the activation of STIM1-mediated store-operated calcium channels. Both calcium releases from stores or calcium influx through store-operated calcium channels have been confirmed to initiate signaling pathways to regulate inflammatory cytokines and immune diseases. In T-cells, agents block calcium influx through store-operated calcium channel attenuated the translocation of NFAT or NFkB and the expression of immune related genes ITPKC  exhibited lower gene expression that may result in the increase of global intracellular calcium concentration via IP3-mediated pathways. Over-activation of calcium-dependent inflammatory cytokines may damage coronary vessel wall and cause to the aneurysm formation. Our results implied that C-allele of ITPKC SNP rs28493229 may passively increase the activation of calcium-dependent signaling pathways that lead to aneurysm formation in KD patients.ITPKC is able to effect cellular expression level of IPITPKC, CASP3, CTLA4, TGF-beta pathways and MMP family… etc ITPKC and CASP3 are involved in the Ca2+/NFAT pathways. These two genes have been shown to associate with susceptibility to KD in the Japanese and European Americans. Consistent with this, we did observe a significant association in the KD patients with aneurysm formation even though the allele frequency is low. What might be the relevance of our findings to the KD? KD patients who are resistant with initial IVIG therapy have higher risk of developing CAL or aneurysm formation. Many inhibitors for Ca2+/NFAT pathways are already in the clinical use. From pharmacology prospective, to identify novel inhibitors against Ca2+/NFAT pathways seems to be promising in the treatment of KD. Further pharmacogenomic studies to confirm to the effects of inhibitors for Ca2+/NFAT pathways such as Cyclosporine A in the IVIG resistant patients may should be considered.KD is considered as one of the immune-mediated diseases. Several genes have been reported to be associated with susceptibility to KD and/or CAL formation including ITPKC (rs28493229) had significant association with the susceptibility of KD in the Taiwanese population. Importantly, KD patients carry ITPKC rs28493229 C allele had significant higher risk to have aneurysm formation.In conclusion, we reported that


Aldosterone synthase (CYP11B2) T-344C gene polymorphism was found to be correlated with atrial fibrillation (AF) risk. However, the results of individual studies remain conflicting.CYP11B2 T-344C gene polymorphisms and AF. The pooled odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were evaluated by the fixed– or random–effects model.A meta-analysis including 2,758 subjects from six individual studies was performed to explore the correlation between CYP11B2 T-344C gene polymorphism and AF was found under allelic , recessive , dominant , homozygous , and additive  genetic models. No significant association between CYP11B2 T-344C gene polymorphism and AF was found under the heterozygous genetic model .A significant relationship between CYP11B2 T-344C gene polymorphism and AF risk. Individuals with the C allele of CYP11B2 T-344C gene polymorphism have higher risk for AF.A significant association was found between  Atrial fibrillation (AF) is the most common and damaging arrhythmia in clinical practice. The prevalence of AF increases with age, from 0.5% of people in their 50s to nearly 10% of the octogenarian population Activation of the rennin-angiotensin-aldosterone system plays a key role in AF formation. Aldosterone is the steroid hormone secreted by the adrenal cortex zona glomerulosa, wherein the classic action pathway is to be combined with the aldosterone receptor in the renal distal convoluted tubule and manifolds. Thus, aldosterone exhibits sodium retention and potassium elimination effects that contribute to increased blood volume, blood pressure, left ventricular pressure, left ventricular volume, left atrial pressure, and left atrial volume. Aside from the indirect effect of aldosterone on the cardiovascular system, aldosterone directly affects the heart. Animal experiments suggested that aldosterone possibly induces cardiac hypertrophy and fibrosis Recent studies have shown that local cardiac tissue could also synthesize and secrete aldosterone. Aldosterone receptors broadly exist in cardiomyocytes, vascular smooth muscle cells (VSMCs), and fibrocytes. The binding of aldosterone to its receptor promotes the differentiation and proliferation of cardiomyocytes and VSMCs. It could also precipitate fibrocyte proliferation and hypertrophy. Hence, collagen production is increased significantly, leading to cardiac fibrosis, remodeling, and arrthythmia. In 1999, Delcayre et al. found that plasma aldosterone could act on angiotensin II receptor, which strengthens the legacy effect after angiotensin II binds to the receptor. Aldosterone could increase the gene expressions of c-fos and c-jun, thereby increasing collagen generation and promoting cardiac fibrosis through activation of the inositol triphosphate pathway Although the pathology of AF has been transited from “locality drive and multiple wavelet foldback” to “locality drive with fibrillatory conduction” and pulmonary wave theory, the mechanism has not been fully clarified yet. Single-nucleotide polymorphisms (SNPs) are DNA sequence polymorphisms caused by single nucleotide variations in the chromosomes, in which at least one allele frequency in the population is not less than 1%. SNPs are the most common human heritable variations aldosterone synthase (CYP11B2) gene located in 8q22 spans approximately 7 kb and contains nine exons and eight introns. CYP11B2, which belongs to the cytochrome P-450 gene superfamily, is the catalytic enzyme of the last biochemical reaction step in vivo to synthesize aldosterone th base thymine (T) is substituted by cytosine (C) at the promoter region, which is the binding site for steroidogenic transcription factor 1. Mutations in the CYP11B2 T-344C gene could elevate serum aldosterone level and increase type I and III collagen gene expressions, which promote fibrosis and cause inconsistent conduction The CYP11B2 T-344C gene polymorphism and AF, their results remain inconsistent. In 2011, Sun et al. CYP11B2 T-344C gene polymorphism is not associated with AF but may be associated with hypertensive atrial remodeling in a Chinese population CYP11B2 T-344C gene polymorphism might play a role in the occurrence of AF in Chinese hypertensive patients. In 2008, Amir et al. CYP11B2 T-344C gene polymorphism is predisposed to clinical AF in Israel.Although several studies investigated the association between CYP11B2 T-344C gene polymorphism and AF  by serial 12-lead electrocardiography (ECG) or 24 h Holter monitoring, case-control or cohort studies published in official journals, and studies that conform to the Hardy-Weinberg equilibrium (HWE). The diagnosis points in ECG were as follows: p wave disappearance and substitution of irregular baseline fluctuation (f wave) with the frequency of 350 to 600 per minute, extremely irregular ventricle rate, and inconsistent QRS complex morphology. The QRS complex would be broader and transformed when the aberrant ventricular conduction appeared. The RR internal is always irregular.The studies were selected based on the following inclusion criteria: studies that evaluate Data were drawn out according to a standard protocol. Repeated publications and studies violating the inclusion criteria or providing insufficient data were excluded. Same data from different studies were only adopted once. The extracted data comprised the following items: first author’s name, publication year, study region, number of genotypes, genotyping methods, study design, matching criteria, and total number of cases and controls.CYP11B2 T-344C gene polymorphism), recessive (CC/TC+TT), dominant (TT/TC+CC), homozygous (CC/TT), heterozygous (TC/TT), and additive (C/T) genetic models were used. The relationship between CYP11B2 T-344C gene polymorphism and AF was compared using odds ratios (ORs) and their corresponding 95% confidence intervals (CIs). Chi-square-based Q-test was used to calculate the between-study heterogeneity, with the significance level set at P<0.10 P<0.05.In the current meta-analysis, allelic , homozygous (Pheterogeneity = 0.813), and additive genetic models (Pheterogeneity = 0.416), the fixed-effects model was used. By contrast, the P value of Q-tests was less than 0.10 under the recessive (Pheterogeneity = 0.05), dominant (Pheterogeneity = 0.079), and heterozygous genetic models (Pheterogeneity = 0.001); thus, the random-effects model was adopted. The combined ORs and summary point of the association between CYP11B2 T-344C and AF were calculated and obtained using Revman 4.2 and STATA 11.0 software. , recessive , dominant , homozygous , and additive  genetic models. However, no significant association between CYP11B2 T-344C gene polymorphism and AF was found under the heterozygous genetic model  (A significant relationship between = 0.361) –2.heterogeneity = 0.14; subgroup 2: OR: 4.27, 95% CI: 2.05–8.87, P = 0.0001). Heterogeneity disappeared in subgroup 1 (2I = 42.6%) (Significant heterogeneity was found under the recessive (P = 0.05), dominant (P = 0.079), and heterozygous (P = 0.001) genetic models. The following meta-regression was subsequently conducted to explore the heterogeneity source. Under the recessive genetic model, the heterogeneity could be explained by study region (P = 0.026), TT  and TC  genotype numbers of AF group sample size, and CC genotype number of control group sample size . According to study region, the whole population was separated into two subgroups. The studies performed in China belonged to subgroup 1 and the others into subgroup 2. In the subgroup analysis stratified by study region, a significant increase in AF risk was detected in both subgroups  .heterogeneity = 0.049) but not in subgroup 2  , TT1 P = 0.064), TC1 (P = 0.081), and CC0 (P = 0.070). According to study region, the whole population was divided into two subgroups under the recessive genetic model. In the subgroup analysis, a significant increase in AF risk was detected in subgroup 1   and 4., TC1 , TT0 (P = 0.013), TC1 (P = 0.011), and CC1 (P = 0.021). No significant increase in AF risk was observed in either of the subgroups P>0.05)  and 5.  and 5.5The publication bias of the individual studies was evaluated by funnel plot and Egger’s test. No visual publication bias was found in the funnel plot . No signCYP11B2 T-344C gene polymorphism and increased AF risk under the allelic (OR: 1.26), recessive (OR: 1.99), dominant (OR: 0.903), homozygous (OR: 1.356), and additive (OR: 1.153) genetic models. Under the heterozygous genetic model, the pooled OR was 1.040, suggesting no significant association between CYP11B2 T-344C gene polymorphism and AF. Overall, a significant association exists between CYP11B2 T-344C gene polymorphism and AF risk. Individuals with the C allele of CYP11B2 T-344C gene polymorphism have higher risk for AF. The negative result under the heterozygous genetic model was possibly associated with the relatively smaller difference between cases and controls in TC genotype number than in CC genotype number proportion.In the current meta-analysis, a significant relationship was found between P>0.05). In addition, the association strength was reduced in the China subgroup . Although the association found in the Israel subgroup was much stronger than that found in the China subgroup, the heterogeneity test was not applicable because only one study in the Israel subgroup was retrieved . Hence, study region was the main source of heterogeneity under the recessive genetic model.Considering the heterogeneity under the recessive, dominant, and heterozygous genetic models, a meta-regression was conducted to explore the heterogeneity source. In the heterogeneity source analysis, under the recessive genetic model, confounding factors such as study region (P = 0.026), TT1 (P = 0.028), TC1 (P = 0.028), and CC0 (P = 0.047) were shown to explain the possible heterogeneity source. The subgroup analysis stratified by study region demonstrated that the heterogeneity disappeared in the China subgroup (P = 0.029), TT1 (P = 0.064), TC1 (P = 0.081), and CC0 (P = 0.070) could explain the heterogeneity source. Among these confounding factors, study region was the main source of heterogeneity. Based on the subgroup analysis stratified by study region, the China subgroup had more heterogeneity . However, the association strength was enhanced .Under the dominant genetic model, study region (P = 0.008), TC1 (P = 0.011), TT0 (P = 0.013), and CC0 ( = 0.021) could explain the heterogeneity source. Among these confounding factors, study region was the key influencing factor. Although no difference between CYP11B2 T-344C gene polymorphism and increased AF risk was found under this genetic model, the heterogeneity was more distinct in the China subgroup  than in the whole population .Under the heterozygous genetic model, study region . The -344C allele binds to SF-1 four times more than the T allele, which is associated with increased serum aldosterone level and AF occurrence CYB11B2 is the limiting-velocity enzyme of the last step in aldosterone biosynthesis. Therefore, the CYP11B2 T-344C gene polymorphism were still relatively inadequate. The CYP11B2 expression level was influenced not only by the CYP11B2 T-344C gene polymorphism, but also by other genetic and environmental factors such as sympathetic nerve activation, inflammation state, and so on. Factors such as age, body mass index, and premeditation in the individual studies were not well matched yet.The current meta-analysis faced some limitations. The studies included for the analysis were small (n = 6). Large-scale studies on the association between AF and CYP11B2 T-344C gene polymorphism is significantly linked with increased AF risk. Patients with the C allele have higher risk for AF. The current conclusion may serve as a basis for the development of individual AF diagnosis and therapy strategies. Given the above limitations, more large-scale studies are needed to elucidate the significance of the verdict.In conclusion, Supplement S1PRISMA 2009 Checklist.(DOC)Click here for additional data file.Supplement S2PRISMA 2009 Flow Diagram.(DOC)Click here for additional data file.


Glutathione S-transferase M1 (GSTM1) is thought to be involved in detoxifying several carcinogens and may play a vital role in tumorigenesis. Numerous studies have evaluated the association between GSTM1 null/present polymorphism and risk of prostate cancer (PCa). However, the results remain inconsistent. To derive a more precise estimation, we performed a meta-analysis.P = 0.001). Moreover, subgroup analyses showed GSTM1 null genotype significantly associated with PCa risk among Asians  but not among Caucasians . In addition, we did not find that smoking modified the genotype effect on the risk of PCa.A comprehensive search was conducted to identify all eligible case-control studies. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. The overall association was significant (OR = 1.28, 95% CI: 1.11–1.48, The present meta-analysis suggested that GSTM1 null allele was a low-penetrant risk factor for PCa among Asians. Prostate cancer (PCa) is now thought to be one of the most important medical problems in the male population Generally, genetic susceptibility could modify the effect of environmental exposure, possibly explaining the difference of PCa incidence rate throughout the world. It is possible that the susceptibility to PCa is determined by the interindividual differences in the bioactivation of procarcinogens and detoxification of carcinogens because of the polymorphisms in metabolic genes. Glutathione S-transferase M1 (GSTM1) is thought to be involved in detoxification of carcinogens, which has been considered as a PCa susceptibility gene GSTM1, located on chromosome 1p13.3, detoxifies numerous electrophilic substances, including carcinogens such as polycyclic aromatic hydrocarbons, ethylene oxide, epoxides, and styrene. GSTM1 expression could be hormonally controlled and induced by phenobarbital or propythiouracil PubMed (1956 to July 2012) and Embase (1947 to July 2012) database search was conducted using the following search terms: “GSTM1 or GST”, “polymorphism or variant”, and “prostate or prostatic”. Additional relevant studies were identified by a hand search of the references of original studies. Of these studies with the same or overlapping data, we selected the most recent ones with the largest number of subjects. Studies included in this meta-analysis should meet the following criteria: (a) evaluation the association of GSTM null/present polymorphism and PCa risk published in English language, (b) case-control study, (c) containing sufficient data for estimation of odds ratio (OR) with 95% confidence interval (95% CI).Two authors independently extracted the data and reached a consensus on all the items. For each study, the following information was collected: first author, publishing year, ethnicity of subjects, source of controls, number of cases and controls, genotyping method. Different ethnic descents were categorized as Caucasians, Asians, and Africans. If a study did not specify the ethnicity or if it was not possible to separate participants according to such phenotype, the group was termed “mixed ethnicity”. For study The strength of the association between GSTM1 null/present polymorphism and PCa risk was measured by ORs with 95% CIs. The statistical significance of the summary OR was determined by the Z-test. For GSTM1 null polymorphism, we estimated the risk of the “Null” genotype on PCa risk, compared with the “Present” genotype. Stratified analyses were performed by ethnicities and smoking status.2-based Q-test. A P value of greater than 0.10 indicates a lack of heterogeneity among studies and the fixed-effects model was used to estimate the pooled OR of each study (the Mantel-Haenszel method). Otherwise, the random-effects model (the DerSimonian and Laird method) was used P<0.05 was considered statistically significant.Heterogeneity was evaluated by χAll statistical tests for this meta-analysis were performed with STATA .For PCa risk related to GSTM1 null polymorphism, articles were retrieved based on the search criteria above. Study selection process is shown in P = 0.001; P = 0.03; P = 0.16; Overall, we found that GSTM1 null genotype was significantly associated with increased risk of PCa , Caucasians .P = 0.08; Begg’s funnel plot and Egger’s test were conducted to assess a possible publication bias in the literature. The shapes of funnel plots did not reveal any evidence of funnel plot asymmetry. The results Egger’s test from showed no indication of publication bias  Although case misclassification bias was unlikely to exist in this study because all PCa cases were confirmed on the basis of histological criteria, we could not exclude the possibility that some control subjects had latent PCa which had not been detectable by PSA analysis or digital rectal examination (DRE). The undetected PCa in controls might produce bias estimates toward the null, and the strength of positive correlation might be underestimated. (ii) Our result was based on unadjusted estimates because of the limited information available. A more precise analysis should be conducted on the basis of adjustment for confounders such as age. (iii) Data on Africans was limited.In summary, this meta-analysis provided the evidence that GSTM1 null genotype might be a low-penetrant susceptibility marker for PCa among Asians.Table S1The characteristics of studies included in the meta-analysis.(DOC)Click here for additional data file.Table S2Main result of pooled ORs in the meta-analysis.(DOC)Click here for additional data file.


COMT) is one of the most important enzymes involved in estrogen metabolism and its functional genetic polymorphisms may be associated with breast cancer (BC) risk. Many epidemiological studies have been conducted to explore the association between the COMT Val158Met polymorphism and breast cancer risk. However, the results remain inconclusive. In order to derive a more precise estimation of this relationship, a large meta-analysis was performed in this study.Catechol-O-methyltransferase  with 95% confidence intervals (CIs) were calculated to estimate the strength of the association.COMT Val158Met polymorphism and breast cancer risk were found for LL versus HH, HL versus HH, LL versus HL, recessive model LL versus HL+HH, and dominant model LL+HL versus HH. In subgroup analysis by ethnicity, source of controls, and menopausal status, there was still no significant association detected in any of the genetic models.A total of 56 studies including 34,358 breast cancer cases and 45,429 controls were included. Overall, no significant associations between the COMT Val158Met polymorphism may not contribute to breast cancer susceptibility.Our meta-analysis results suggest that the http://www.diagnosticpathology.diagnomx.eu/vs4806123577708417The virtual slides(s) for this article can be found here:  BRCA1 and BRCA2 mutations have been reported to be associated with a dominantly inherited increased risk of the disease. However, they only account for about 5% of breast cancer occurrences [Breast cancer is one of the most frequently occurring cancer and cancer-related deaths are highly prevalent worldwide, which has become a major public health challenge . The mecCOMT) is an important phase II enzyme involved in the conjugation and inactivation of catechol estrogens [COMT is expressed at high levels in a variety of human tissues including liver, kidney, breast, and red blood cells [COMT gene is located on chromosome 22q11 [COMT gene results in valine to methionine amino acid change in codon 108/158 in the cytosolic/membrane-bound form of the protein. This amino acid change is believed to result in a 3–4-fold decrease in enzymatic activity [COMT compared with the wildtype , these two forms are represented as COMT-L allele and COMT-H allele, respectively. It has been hypothesized that the individuals who inherit the low activity COMT-L gene may be at increased risk for breast cancer because of an increased accumulation of the catechol estrogen intermediates [Catechol-O-methyltransferase , Embase (http://www.embase.com/) and Cochrane Library (http://www.thecochranelibrary.com/view/0/index.html) were used to search for all genetic association studies evaluating the COMT Val158Met polymorphism and breast cancer risk up to February 2012, the search strategy was based on combinations of “Breast cancer”, “Catechol-O-methyltransferase”, “COMT”, “polymorphism”, and “mutation”. No language or country restrictions were applied. All eligible studies were retrieved, and their bibliographies were checked for other relevant publications. Review articles and bibliographies of other relevant studies identified were searched by hand to find additional eligible studies. When multiple publications reported on the same or overlapping data, we chose the most recent or largest population. When a study reported the results on different subpopulations, we treated it as separate studies in the meta-analysis.Electronic databases PubMed  case–control design; (3) sufficient data for estimating an odds ratio (OR) with 95% confidence interval (CI); and (4) studies with full text articles. Studies were excluded if one of the following existed: (1) no control population; and (2) duplicate of previous publication.Studies included in our meta-analysis had to meet the following inclusion criteria: (1) evaluate the association between P value for control population in Hardy–Weinberg equilibrium (HWE). We did not define any minimum number of patients to include in our meta-analysis.Information was carefully extracted from all eligible publications by two investigators (Xue Qin and Qiliu Peng) independently according to the inclusion criteria listed above. For conflicting evaluation, an agreement was reached following discussion during a consensus meeting with a third reviewer (Aiping Qin). For each study, the following information were collected: First author’s name, year of publication, country, ethnicity of the studied population, total numbers of cases and controls, breast cancer diagnosis criteria, matching criteria, genotyping method, menopausal status, sources of the control population, quality control of genotyping and COMT Val158Met polymorphism and breast cancer risk. The pooled ORs were performed for co-dominant model , dominant model (LL+ HL vs. HH), and recessive model (LL vs. HL+HH), respectively. Departure from the Hardy–Weinberg equilibrium for the control group in each study was assessed using a web-based program (http://ihg2.helmholtz-muenchen.de/cgibin/hw/hwa1.pl). In subgroup analysis, we evaluated the effect of COMT Val108/158Met polymorphism on the susceptibility of BC in different population stratified by ethnicity , menopausal status  and sources of the control population .Crude odds ratios (ORs) together with their corresponding 95% CIs were used to assess the strength of association between the Q-statistic test was used to evaluate the between-study heterogeneity of the studies. If P < 0.10, the between-study heterogeneity was considered to be significant, we chose the random-effects model to calculate the OR. Otherwise, when P ≥ 0.10, the between study heterogeneity was not significant, then the fixed effects model was used. We also measured the effect of heterogeneity using a quantitative measure, I2 = 100% × (Q – df)/Q[I statistic measures the degree of inconsistency in the studies by calculating what percentage of the total variation across studies is due to heterogeneity rather than by chance [P < 0.10 or I2 > 50%) or absence (P ≥ 0.10 and I2 ≤ 50%) of heterogeneity, respectively.For each genetic comparison, a chi-square-based Q – df)/Q. The I s chance . FinallyP ≥ 0.05 suggests no bias). All analyses were performed using Stata software, version 10.0 .Cumulative meta-analysis was conducted to identify the influence of the first published study on the subsequent publications, and the evolution of the combined estimates over time according to the ascending date of publication. To identify potentially influential studies, sensitivity analysis was also performed by excluding the studies without definite diagnostic criteria, the studies without quality control when genotyping and the studies whose genotype frequencies in control populations exhibited significant deviation from the Hardy–Weinberg equilibrium (HWE), given that the deviation may denote bias. The funnel plots and Egger regression asymmetry test were used to assess publication bias. Egger’s test can detect funnel plot asymmetry by determining whether the intercept deviates significantly from zero in a regression of the standardized effect estimates against their precision. A T test was performed to determine the significance of the asymmetry. An asymmetric plot suggested possible publication bias . There were 22 comparisons concerned with COMT Val158Met polymorphism and premenopausal BC patients and 27 comparisons concerned with COMT Val158Met polymorphism and postmenopausal BC patients (see Table BC diagnosis. Eighty-two (46/56) percent of the control populations matched to BC patients with age and 52% (29/56) studies used the classic PCR-RFLP assay to genotype the COMT Val158Met polymorphism, about 52% (29/56) of the case–control studies included mentioned the quality control when genotyping. The genotype frequencies of control group in 3 studies were not consistent with HWE [P value of HWE in two studies [P value of HWE in the control group could not be calculated.According to our search criteria, 61 studies relevant to the role of  review , four we review -25, four review -29, and orphism . Manual orphism ,31-73. Aorphism ,56,60,69ith HWE ,41,70. Wstudies ,73 becauCOMT Val158Met polymorphism and breast cancer susceptibility were observed in all genetic models when all the eligible studies were pooled into the meta-analysis. No significant associations were found for LL versus HH , HL versus HH , LL versus HL , recessive model LL versus HL+HH  and dominant model LL+HL versus HH . Next, the effect of COMT Val158Met polymorphism on breast cancer risk was evaluated according to ethnicity, menopausal status . The results indicated that the results of these meta-analyses are relatively stable and that publication bias is unlikely to affect the results of the meta-analyses.Begg’s funnel plots and Egger’s tests were performed to assess publication bias. The shapes of the funnel plots revealed no obvious asymmetry Figure . The EggCOMT) catalyzes the O-methylation of these carcinogenic estrogens to methoxyes tradiols and methoxyestrones. In the COMT gene, a G to A transition results in an amino acid change  at codon 108 of soluble COMT and codon 158 of membrane-bound COMT. This amino acid change is believed to result in a 3–4-fold decrease in enzymatic activity [COMT Val108/158Met polymorphism and the risk of subsequent BC has evoked a huge interest from clinicians, scientists, and the public. During the past few years a large number of studies with case–control design have been carried out to investigate this topic but consistent results have not been reported. We therefore conducted a meta-analysis of the evidence obtained from all published studies in order to elucidate and provide a quantitative reassessment of the association. To our knowledge, this is the most comprehensive meta-analysis to date to evaluate the association between COMT Val108/158Met polymorphism and breast cancer risk.Estrogens, estrone, and estradiol are catabolized to catechol estrogens. Estrogen metabolites, such as 4-hydroxyestrone and 4-hydroxyestrone, shown to be involved in breast carcinogenesis . Catechoctivity ,7. It haCOMT Val108/158Met polymorphism and breast cancer risk either overall or among subgroups of women defined by ethnicity, menopausal status or sources of the control population. In previous studies, overall the findings were inconsistent. Lavigne et al. observed a large increase in the risk of breast cancer among postmenopausal obese women carrying the COMT-LL genotype, and an inverse association among premenopausal women with the relative risk (RR) for COMT-LL stronger among postmenopausal women with high BMI [COMT-HL and COMT-LL genotypes among premenopausal women and found that modification of RRs by BMI was highest among premenopausal women with a high BMI [CYP17, CYP1A1, COMT) also reported that breast cancer is only associated with the low activity COMT genotype in women with a high BMI and that the COMT-LL genotype was strongly associated with breast cancer risk, with an adjusted OR of as high as 4.02 [COMT-L allele and breast cancer risk, and did not find strong modification of RR estimates by menopausal status [COMT Val108/158Met polymorphism on breast cancer risk, two previous meta-analyses [COMT Val108/158Met polymorphism and breast cancer. Ding et al. [COMT Val158Met polymorphism on breast cancer risk by combining results in meta-analysis. They concluded that COMT Val158Met polymorphism was significantly associated with increased breast cancer risk in European population. However, Mao et al. [COMT Val158Met polymorphism and breast cancer risk in any genetic models including among Caucasian, Asian, premenopausal, and postmenopausal women in their meta-analysis, which was consistent with the findings of our study. The discrepancy in previously reported findings was most probably because that the previous studies with relatively small sample size may have insufficient statistical power to detect the exact effect or may have generated a fluctuated risk estimate. However, in our study, large number of cases and controls were pooled from all published studies, which greatly increased statistical power of the analysis and provided enough evidence for us to draw a safe and reliable conclusion.We did not observe a positive relationship between igh BMI . Thompsoas 4.02 . In cont status . In an enalyses  were con et al.  examinedBRCA variants). Finding of the source of heterogeneity is one of the most important goals of a meta-analysis. Therefore, we stratified the studies according to ethnicity, source of control subjects of the studies, and menopausal status. Subsequent subgroup analysis stratified by ethnicity, source of control subjects, and menopausal status identified large heterogeneity as well, indicating that menopausal status, ethnicity or source of control subjects contributed little to the existence of overall heterogeneity. Unfortunately, our study had insufficient information for subgroup analysis to detect whether the variants in BRCA gene might be great sources of heterogeneity. We found that in three studies [COMT Val158Met polymorphism and breast cancer risk.Heterogeneity is a potential problem that may affect the interpretation of the results. The present meta-analysis showed that there was large heterogeneity between studies table . Common studies ,41,70 thstudies ,73 provistudies . In our COMT Val108/158Met polymorphism and breast cancer risk in several subgroups of populations, such as associations among postmenopausal women with a low body mass index (BMI) [COMT polymorphisms. In spite of these, our present meta-analysis also had some advantages. First, substantial number of cases and controls were pooled from all publications concerned with COMT Val158Met polymorphism and BC risk, which greatly increased statistical power of the analysis and provided enough evidence for us to draw a safe conclusion. Second, the quality of case–control studies included in this meta-analysis was satisfactory according to our selection criteria. Third, no publication bias was detected in this meta-analysis, which indicated that the pooled results of our study should be reliable.Some limitations of this meta-analysis should be acknowledged. First, some studies found significant associations between x (BMI) , a high x (BMI)  or womenx (BMI) . It is dCOMT Val158Met polymorphism may not be associated with breast cancer risk. However, it is necessary to conduct large sample studies using standardized unbiased genotyping methods, homogeneous breast cancer patients, and well-matched controls. Moreover, gene-gene and gene-environment interactions should also be considered in the analysis. Such studies taking these factors into account may eventually lead to a better, more comprehensive understanding of the association between COMT Val158Met polymorphism and BC risk.In conclusion, this meta-analysis suggests that the BC: Breast cancer; HWE: Hardy–Weinberg equilibrium; OR: Odds ratio; CI: Confidence interval; COMT: Catechol-O-methyltransferase; BMI: Body mass index; PB: Population-based; FB: Family-based; HB: Hospital-based; Pre: Premenopausal; Post: Postmenopausal; PCR-RFLP PCR: based restriction fragment length polymorphism; MALDI-TOF MS: matrix assisted laser desorption/ionization time-of-flight mass spectrometry; LP: Luorescence polarization.The authors declared that they have no conflict of interest in relation to this study.All authors have read and approved the final files for this manuscript.


Objective. Recent studies on the association between uridine diphosphosglucuronosyltransferases (UGTs) 2B17 polymorphism and risk of prostate cancer (PCa) showed inconclusive results. To clarify this possible association, we conducted a meta-analysis of published studies. Methods. We searched the published literature from PubMed, Embase, Google Scholar, and China National Knowledge Infrastructure (CNKI). According to our inclusion criteria, studies that observed the association between UGT2B17 polymorphism and PCa risk were included. The principal outcome measure was the adjusted odds ratio (OR) with 95% confidence interval (CI) for the risk of PCa associated with UGT2B17 polymorphism. Results. A total of 6 studies with 7,029 subjects  were eligible for inclusion in the meta-analysis. Overall, there was a significant association between UGT2B17 polymorphism and increased risk of prostate cancer . Similar results were found in the subgroup analyses by ethnicity and types of controls. Conclusion. This meta-analysis demonstrates that UGT2B17 polymorphism is associated with prostate cancer susceptibility, and it contributes to the increased risk of prostate cancer. UGT2B17 gene [Prostate cancer is the fourth most common cancer in men, comprising approximately one-eighth of all male-specific cancers in the world . IdentifB17 gene , 22.To date, a number of molecular epidemiological studies have been conducted to evaluate the effect of the UGT2B17 deletion on risk of prostate cancer –28. HoweRelevant studies to be included in the study were searched from the following databases PubMed, Embase, Google Scholar, and China National Knowledge Infrastructure (CNKI). The search was conducted in December, 2012. Relevant publications were identified using the following search strategies: “Uridine diphosphoglucuronosyl tranferases 2B17” or “UGT2B17” or “UGT2B17 deletion” or “polymorphism” and “prostate cancer” or “prostate carcinoma”. Additional literature was collected from cross references of both original and review articles. Only original published studies with fulltext articles were included.All human associated studies were included, if they met the following criteria: (1) evaluation of the UGT2B17 present/null polymorphism and prostate cancer risk, (2) case control studies, (3) report on an OR with 95% CI, and (4) being original and published in English with an availability of a full-text. Exclusion criteria were (1) insufficient original data for the calculation of odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs), (2) not case control study, and (3) review studies.Information was carefully extracted from all the eligible publications independently by two authors according to the criteria listed previously. Disagreements were resolved by discussion among all authors. The following information was recorded for each study: first author, year of publication, country or region of origin, ethnicity, OR (95% CI), number of cases and controls, source of control group , and genotype frequency of UGT2B17. For studies that included subjects of different ethnic descents, data were extracted separately for each ethnicity, which was categorized as Caucasian, Whites, and African Americans.Z-test. Heterogeneity assumption was checked by the Chi-square test based Q statistic [I2 statistic [Q statistic (P < 0.10) or I2 statistic (I2 > 50%) indicated obvious heterogeneity across studies, and the random-effect model was selected to pool the ORs. Otherwise, the fixed-effect model was selected to pool the ORs. Subgroup analyses were performed by ethnicity and types of controls. Subgroup analyses were firstly performed by ethnicity, and ethnicities were categorized as Caucasians, Whites, and African Americans. Finally, subgroup analyses were performed by the types of controls. Sensitivity analysis was performed to assess the stability of results. Publication bias was investigated with the funnel plot. The funnel plot should be asymmetric when there is a publication bias, and the funnel plot asymmetry was further assessed by the method of Egger's linear regression test [The strength of the association between UGT2B17 polymorphism and prostate cancer risk was assessed by calculating the pooled OR with its 95% CI. The pooled ORs were obtained using either the fixed-effect (Mantel-Haenszel's method)  or randotatistic  and the tatistic . A signiion test . All staThe flow chart of study selection for this meta-analysis is presented in The main characteristics of the included studies are presented in P < 0.001)  . P = 0.026) (P = 0.011) . There was an obvious association between UGT2B17 polymorphism and increased risk of prostate cancer in Caucasians  . In the = 0.011) .P = 0.026 and I2 = 91.4% for Caucasians) and sources of controls . UGT2B17 polymorphism was significantly associated with prostate cancer risk in overall analysis (I2 = 87.4%).To examine the effect of heterogeneity between studies included in the meta-analysis results, subgroup analyses stratified by the following factors were conducted: ethnicity and sources of controls. The results were as follows: ethnicity  [P = 0.026. Ethnicity is a well-established confounding factor for prostate cancer risk. It was previously reported that the UGT2B17 deletion polymorphism was not associated with an increased risk of prostate cancer in African-Americans from Arkansas [UGT2B15 alleles that are associated with an increased risk of prostate cancer are more common in Asian populations than in Caucasian populations. Obviously, the genetic variation in UGT2B17 (and UGT2B15) does not explain the ethnic differences observed in prostate cancer that was discussed previously [The UGT2B17 enzyme is particularly active in androgen glucuronidation and is highly expressed in prostate tissue , 20, 37. = 0.05) . It is kArkansas  but was Arkansas . ObviousArkansas . The inteviously . AdditioP < 0.001. The possible reason may be that UGT2B17 polymorphism could influence the susceptibility to noncancer diseases, so its genotype frequency possibly differed between the hospital-based and population-based controls. Also the small sample size of population based in this meta-analysis should be taken into consideration.Furthermore, the results of this meta-analysis showed that UGT2B17 polymorphism has strikingly increased the risk of prostate cancer risk susceptibility when stratified by control source. However, we obtained the highest risk of prostate cancer in hospital-based controls with OR = 1.96 (1.16–3.31) and If significant heterogeneity is present, pooled summary estimates from such meta-analyses are hard to interpret. In our meta-analysis, obvious heterogeneity across studies was observed in the overall comparison and some group analyses.The current meta-analysis has vital advantages compared to other studies; however, there are some limitations in this meta-analysis. Firstly, only published studies in English with full text were included in this meta-analysis; therefore, the publication bias may have occurred. Secondly, the small sample size in subgroup analyses may have limited statistical power. Furthermore, due to limited studies included in this meta-analysis, we were unable to perform further subgroup analyses such as by genotyping method. Thirdly, the results of subgroup analysis should be interpreted with caution because of the limited statistical power. We anticipate that issues will be addressed in future studies. Finally, most studies in the meta-analysis were retrospective design which could suffer more risk of bias owing to the methodological deficiency of retrospective studies. Though there was no obvious risk of publication bias in the present meta-analysis, the risks of other potential bias were unable to be excluded. Therefore, more studies with prospective design and low risk of other bias are needed to provide a more precise estimate of the association between UGT2B17 polymorphism and prostate cancer.In summary, this meta-analysis with a total of 3,839 cases and 3,190 controls suggests that the UGT2B17 polymorphism is associated with increased risk of prostate cancer in Caucasians; well-designed studies with large sample sizes involving various ethnic populations are warranted.


The influence of the risk allele A at rs10486567 was higher in the presence of the risk allele A at rs4242382 (OR = 1.09 (1.01–1.18) vs. 1.01 (0.95–1.07)). Similar findings were observed in non-aggressive PrCa, but not in aggressive PrCa. We demonstrated that two loci (rs4242382 and rs10486567) are highly associated with familial multiple PrCa, and the gene-gene interaction or statistical epistasis was consistent with the Fisher's multiplicative model. These loci's association and epistasis were observed for non-aggressive but not for aggressive tumors. The proposed statistical model can be further developed to accommodate multi-loci interactions to provide further insights into epistasis.Understanding the impact of multiple genetic variants and their interactions on the disease penetrance of familial multiple prostate cancer is very relevant to the overall understanding of carcinogenesis. We assessed the joint effect of two loci on rs4242382 at 8q24 and rs10486567 at 7p15.2 to this end. We analyzed the data from a Finnish family-based genetic study, which was composed of 947 men including 228 cases in 75 families, to evaluate the respective effects of the two loci on the disease penetrance; in particular, the occurrence and number of prostate cancer cases within a family were utilized to evaluate the interactions between the two loci under the additive and multiplicative Poisson regression models. The risk alleles A at rs4242382  and a risk allele A at rs10486567  were found to be associated with an increased risk of familial PrCa, especially with four or more cases within a family. A multiplicative model fitted the joint effect better than an additive model (likelihood ratio test X JAZF1 gene at 7p15.2 has been repeatedly associated with PrCa risk Genetic predisposition and familial aggregation of prostate cancer (PrCa) have been demonstrated in numerous studies; a twin study showed a very high heritability score JAZF1, which encodes a transcriptional repressor of NR2C2, a nuclear orphan receptor that is highly expressed also in prostate cancer The SNP known as rs10486567 is located within the intron 2 of the JAFZ1 on chromosome 7 with consistent associations in various populations and also with different disease outcomes.Because a number of SNPs are involved in familial risk for prostate cancer, but their independent main effects explain only a fraction of the observed heritability, gene-gene interaction between loci  provides a potential improvement in understanding the hereditary component of prostate cancer We aimed to evaluate the impact of two loci on rs4242382 and rs10486567 on the prostate cancer risk within a family. We also evaluated interactions between the two loci in additive and multiplicative models. Separate analyses were also conducted for aggressive and non-aggressive PrCa.The data used for the following analysis are from a population-based cohort that consisted of patients diagnosed with prostate cancer in the Pirkanmaa Hospital District and control subjects selected from the anonymous male blood donors obtained from the Finnish Red Cross. The study design and the DNA sample collection have been described in previous studies JAZF1) is commonly observed in the Europeans Two loci, rs4242382 at 8q24 and rs 10486567 at 7p15.2, with genotypes AA, GA, and GG, were selected for the analysis for the reasons outlined above. The risk allele A of rs4242382 at 8q24 has been previously reported to be associated with an aggressive PrCa The frequencies of the two SNPs were expressed as percentages. The frequencies of the genotype AA or GA versus GG are listed by the number of affected men for the two loci. By taking the number of PrCa cases among the family members of a proband as the outcome, we used a multi-variable Poisson regression model to evaluate the effect of the genotypes AA/GA versus GG for the two SNPs on the number of PrCa cases in the family. In addition, we evaluated the gene interactions between the two SNPs under the two models of statistical epistasis, the additive model and multiplicative model proposed by Fisher. We used the likelihood ratio test with Akaike Information Criterion (AIC) measures to assess whether an additive or a multiplicative model fitted the data better when it included the two loci vs. only one locus.The allele frequencies were calculated as 6.4% of AA (n = 61), 31.8% of GA (n = 301), and 61.8% of GG (n = 585) for rs4242382; 6.5% of AA (n = 61), 36.9% of GA (n = 348), and 57.6% of GG (n = 534) for rs10486567.The frequency of the risk allele A (AA or GA) at rs4242382 increased from 34.2% for families with two PrCa cases up to 53% for family families with at least five affected members . SimilarIn the Poisson regression analysis considering age as a confounding factor, the risk allele A at rs4242382 was associated with an increased risk of familial multiple PrCa cases  = 183.0093, P<0.0001, and the A at rs10486567 with X2(1) = 16.89, P<0.0001, When the two loci were considered simultaneously in an additive model, the regression coefficients were slightly decreased from aOR = 1.14 (1.08–1.19) to aOR = 1.13 (1.08–1.19) for the risk allele A at rs4242382, as well as from aOR = 1.06 (1.01–1.11) to aOR = 1.04(1.00–1.09) for the risk allele A at rs10486567. Adding either risk allele improved the fit of the model at a statistically significant level compared with a single locus model  on the disease penetrance by using the state-of-the-art statistical analysis of joint effects. Furthermore, our end-point was multiple PrCa cases within a family, which has rarely been studied. Epistasis in genotype level is defined as the interaction among multiple genes or loci, and this joint genetic effect may be the factor behind “missing heritability”, a phenomenon linked to the unexplained portion of hereditary cancer susceptibility, which is observed in PrCa. In the current study, we used family-based data to investigate the effect of two loci, rs4242382 at 8q24 and rs10486567 at 7p15.2, on multiple PrCa cases within families with the Poisson regression method to compare additive and multiplicative models. We demonstrated a statistically significant association between the two individual loci and multiple PrCa, as well as a synergistic gene-gene interaction between the two risk alleles. Gene-gene interactions were statistically significant under both models, but the multiplicative model provided a better fit than the additive model with respect to the likelihood ratio test with the AIC criterion. The genetic interactions (joint effect of rs4242382 at 8q24 and rs10486567 at 7p15.2) resulted in a positive statistical epistasis (enhancement) in the multiplicative model but a slightly negative epistasis (antagonistic effect) in the additive model. This statistical epistasis was also observed for non-aggressive PrCa, but not for the aggressive PrCa.JAZF1 gene on chromosome 7p15.2 encodes a three C2-H2-type zinc finger protein, which is a transcriptional repressor of NR2C2, a nuclear orphan receptor that is highly expressed in prostate tissue and interacts with the androgen receptor. There is no biological interpretation for the functional implications of JAZ1 in prostate carcinogenesis. It has been reported that JAZF1 is a component of gene fusion with SUZ12, which is found in endometrial stromal tumor. The inverse association found in both Thomas's and our study may be due to the increased risk for T2D, which has been reported to be inversely associated with PrCa JAZF1 is known to have alternatively spliced variants, which encode for different protein isoforms but not all variants have been fully characterized. These may be tissue type and/or SNP specific. However, no explicit conclusions about the interactions between these variants can be made without further functional validation. The results presented here were from a relatively small sample set and therefore additional studies are warranted, also in other populations.Our findings for rs4242382 at 8q24 and rs 10486567 at 7p15.2 were consistent with the genome-wide study in which the risk allele A of rs4242382 at 8q24 led to a 41% increase in the risk of non-aggressive PrCa and a 66% risk increase in the aggressive PrCa compared with the control group; the risk allele G of rs10486567 at 7p15.2 was associated with a 18% decrease in non-aggressive PrCa and 8% decrease in the aggressive PrCa A family-based study design is ideal for assessing the independent genetic influence of several SNPs and their joint effects with other genetic determinants on the disease penetrance among multiple PrCa cases. It can also provide an insight into the functional and evolutionary consequences of epistasis.We tested gene interactions between the two loci, rs4242382 at 8q24 and rs 10486567 at 7p, under the Fisher's model of statistical epistasis, and we found that the multiplicative model fitted the findings better than the additive model. This suggests the presence of linkage disequilibrium for these two loci In conclusion, we proposed a family-based study design to demonstrate the effect of the previously reported SNP at 8q24, known as rs4242382, on the risk of multiple PrCa. Our findings suggest an interaction between rs4242382 and rs10486567 in both multiplicative and additive models. The proposed method is useful for identification of relevant variants in strong LD with the SNP of interest as well as quantifying epistasis between two loci affecting the penetrance of complex diseases and their traits.File S1Table S1, Likelihood ratio test for two loci with and without interaction models of prostate cancer. Table S2, Likelihood ratio test for two loci with and without interaction models of non-aggressive prostate cancer. Table S3, Likelihood ratio test for two loci with and without interaction models of aggressive prostate cancer.(DOC)Click here for additional data file.