The hypoxia-inducible factor-1 alpha (HIF1A) plays a vital role in cancer initiation and progression. Previous studies have reported the existence of HIF1A P582S and A588T missense polymorphisms in renal, urothelial and prostatic carcinomas, however the effects remain conflicting. Therefore, we performed a meta-analysis to assess the association between these sites and the susceptibility of urinary cancers.We searched the PubMed database without limits on language until Nov 25, 2012 for studies exploring the relationship of HIF1A P582S and A588T polymorphisms and urinary cancers. Still, article search was supplemented by screening the references of retrieved studies manually. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to evaluate the strength of the associations between the two by RevMan 5.0 software. Simultaneously, publication bias was estimated by funnel plot and Begg’s test with Stata 12.1 software.Pheterogeneity = 0.11, P = 0.02). For HIF1A A588T polymorphism, the A allele was significantly correlated with higher urinary cancers risk in Asian population . Still, significant associations were found for prostate cancer in the allele and dominant models .Overall, 11 individual case-control studies with 5195 cases and 5786 controls for P582S polymorphism, and 9 studies with 3482 cases and 4304 controls for A588T polymorphism were respectively included in the final meta-analysis. For HIF1A P582S polymorphism, individuals with TT genotype showed 1.60 fold higher risk than the others carrying CT or CC genotypes in Caucasian population (OR = 1.60, 95% CI = 1.09–2.33, The current findings suggest that HIF1A P582S polymorphism correlates with urinary cancers risk in Caucasian population, while A588T polymorphism may increase the risk of urinary cancers in Asian population and prostate cancer. Cancer, known as a malignant neoplasm, is involving in unregulated cell growth. Approximately 12.7 million cancers were newly diagnosed and 7.6 million people died of cancer worldwide et al found that HIF1A P582S and A588T polymorphisms would confer susceptibility to RCC. Still, three additional studies by Foley R et al demonstrated that men with HIF1A P582S polymorphism had a higher risk of prostate cancer. Li P et al reported that HIF1A A588T rather than P582S polymorphism contributed to increased risk of prostate caner. In contrast, Nadaoka J et al showed the data that these polymorphisms correlated closely with the progression of transitional cell carcinoma (TCC) and renal cell carcinoma (RCC) but the onset of TCC and RCC. Jacobs EJ et al even indicated that the rate of A588T polymorphism was lower in prostate cancer patients. Meanwhile, several studies done by other groups Hypoxia refers to low oxygen condition and is common in solid tumors The inconsistent conclusions may have resulted from differences in patient ethnic backgrounds and relatively small sample sizes. In this study, we collected and summarized published case-control studies on the two most widely studied polymorphisms in urinary cancers to shed light on current uncertain claims.th, 2012. Epidemiologic studies exploring the relationship of HIF1A P582S and/or A588T polymorphisms and urinary cancers were identified. The following keywords were adopted: (hypoxia-inducible factor-1 OR hypoxia-inducible factor OR HIF-1 OR HIF1A OR HIF) and (polymorphism OR variant OR SNP OR mutation) and . Meanwhile, the references of eligible studies were manually screened for potential case-control studies. Finally, a total of 248 abstracts meeting the search criteria were retrieved. The eligibility criteria of the meta-analysis were: (a) The studies had to be case-control studies exploring the associations between HIF1A P582S and/or A588T polymorphisms and urinary cancers; (b) The studies provided the number of cases and controls for various genotypes. The exclusion criteria of the meta-analysis were: (a) animal studies; (b) reviews, editorial, comments; (c) studies with duplicate data. On screening titles, abstracts and full texts, 11 eligible studies conformed to inclusion criteria were finally included.In current meta-analysis, the database of PubMed was scrutinized without limits on language until Nov 25For each study, we extracted data through a standard form. The following characteristics were respectively extracted from the included studies: name of first author, year of publications, country of origin, ethnicity, gender of recruited subjects, cancer types, numbers of various genotypes in case and control groups, methods for detecting HIF1A P582S and/or A588T polymorphisms, Hardy-Weinberg equilibrium (HWE). In the case of disagreement, discrepancies of included studies were resolved by discussion.P-value less than 0.05 was considered to be statistically significant. We evaluated the contribution of HIF1A P582S and A588T polymorphisms to the risk of urinary cancers by adopting the RevMan software 5.0, which is developed by Cochrane Collaboration. For HIF1A P582S polymorphism, we evaluated the risk in the dominant model (TT+CT vs. CC), the recessive model (TT vs. CT+CC) and the allele model (T vs. C) respectively. For HIF1A A588T polymorphism, we only evaluated the risk in the dominant model (AA+AG vs. GG) and the allele model (A vs. G) due to few frequencies of genotype AA in subjects. Then, we performed subgroup meta-analysis according to the status of HWE, cancer type and ethnicity. The strength of association was estimated by calculating ORs and the corresponding 95% CIs. Still, a P-value less than 0.05 was considered to be statistically significant. Heterogeneity assumption was assessed by the chi-square based Q test and was regarded to be statistically significant if P<0.10. The random-effects model (the Dersimonian-Laird method) would be used if the test of heterogeneity was significant; otherwise the fixed-effects model (the Mantel-Haenszel method) would be applied in the analysis P-value less than 0.05 was considered to be statistically significant.The genotypes and alleles difference of HIF1A P582S and A588T polymorphisms in Caucasian and Asian populations was calculated by chi-square test. HWE for HIF1A P582S and A588T polymorphisms of control groups was extracted from the original studies. In case of studies without reporting HWE status, HWE in control group was calculated by the chi-square test. And a Overall, a total of 248 abstracts meeting the search criteria were retrieved through PubMed. After screening titles, abstracts and full texts, we identified 11 qualified case-control studies exploring the relationship of HIF1A P582S and/or A588T polymorphisms and urinary cancers. The flow diagram of search strategy in this meta-analysis was shown in As for HIF1A P582S polymorphism, 1106 controls of Caucasian population and 1803 controls of Asian population were included in the meta-analysis. The frequencies of the C and T alleles for Caucasian were 80.74%, 19.26%, while those for Asian were 95.90% and 4.10%, respectively . The freAs for HIF1A A588T polymorphism, The frequencies of the AA+AG and GG genotypes for Caucasian were 6.72%, 93.28% respectively, while those for Asian were 6.11% and 93.89%. The frequency distributions of the genotypes for HIF1A A588T polymorphism were statistically insignificant between the Caucasian and Asian groups. The frequencies of the A and G alleles for Caucasian were 3.84%, 96.16%, while those for Asian were 2.61% and 97.39%, respectively . The frePheterogeneity = 0.00, P = 0.52), the recessive model  and the allele model . Secondly, we performed subgroup meta-analysis based on the difference of ethnicity, cancer type and HWE status. We found that subjects with TT genotype had 1.60 fold higher risk than those with CC or CT genotype in Caucasian population . The remaining subgroup pooled ORs from this analysis were insignificant   .Pheterogeneity = 0.00, P = 0.28) and the allele model . Subsequently, we performed subgroup meta-analysis based on the difference of ethnicity, cancer type and HWE status. We found that subjects carrying A allele had 1.45 fold higher risk than those with GG genotype in prostate cancer . Still, significant associations were found in the allele model in prostate cancer , prostate cancer in HWE  and Asian population . The remaining subgroup pooled ORs from this analysis were insignificant   .P<0.10), and results were listed in Pheterogeneity = 0.04, P = 0.65) (Significant heterogeneity was observed in some comparisons ( = 0.65) . The othP>0.05). The results of Begg’s test in the dominant model for HIF1A P582S and A588T polymorphisms were shown in The potential publication bias was firstly appraised by the funnel plot which showed no apparently asymmetric. Still, the results of Begg’s test revealed no publication bias . Still, a significant association was found for prostate cancer in allele model . A marginal significant association between the two was detected for prostate cancer in the dominant model by analyzing only studies with controls in HWE . The remaining pooled ORs from this analysis were insignificant . Studies for mechanism found that A588T variant showed a higher transactivation capacity than WT under either normoxic or hypoxic condition HIF1A A588T, also termed as Ala588Thr, G1790A, rs11549467, is located within the oxygen-dependent degradation domain (ODD) which spans from amino acid 401 to 603. In normoxia, HIF1A is hydroxylated on Pro402 and Pro564 followed by interaction with VHL to initiate rapid ubiquitination and proteasomal degradation. This may be one of the precise mechanisms that HIF1A A588T polymorphism plays its effect. In our study, the A allele was significantly correlated with higher urinary cancers risk in Asian population . The remaining pooled ORs from this analysis were insignificant . Studies for mechanism found that P582S variant showed a higher transactivation capacity than WT under either normoxic or hypoxic condition Pheterogeneity = 0.33, P = 0.65). Because the results of the sensitivity analysis excluding studies not in HWE would be more reliable HIF1A P582S, also termed as Pro582Ser, C1772T, rs11549465, is located in exon 12 near Pro564 within the ODD, which is supposed to affect the hydroxylation of Pro564 as HIF1A A588T. Additionally, this position is also located near the N-terminal transactivation domain (TAD-N), which spans from amino acid 531 to 575. Transcriptional activity of HIF-1 is facilitated by TAD-N and TAD-C in HIF1A and one another in HIF1B. In our study, individuals with TT genotype showed 1.60 fold higher risk than the other carrying CT or CC genotypes in Caucasian population . As for HIF1A P582S polymorphism, 1106 controls of Caucasian and 1803 controls of Asian population were included in the meta-analysis. The frequencies of the T, CT, TT and CT+TT for Caucasian were 19.26%, 23.15%, 7.69%, and 30.83% respectively, higher than those for Asian population 4.10%, 7.99%, 0.11%, and 8.1%. As for HIF1A A588T polymorphism, 1041 controls of Caucasian and 1800 controls of Asian population were included in the meta-analysis. The frequencies of A and AA+AG for Caucasian were 3.84%, 6.72% respectively, while those for Asian were 2.61% and 6.11%. The frequency distributions of the alleles for HIF1A A588T polymorphism were statistically significant between the Caucasian and Asian groups.The current evidences suggest that HIF1A P582S polymorphism may correlate with urinary cancers risk in Caucasian population, while HIF1A A588T polymorphism increases the risk of urinary cancers in Asian population. Ethnicity may be an essential biological factor which influences HIF1A P582S and/or A588T polymorphisms through gene-gene interactions. As we presented in Some studies reported that HIF1A P582S and A588T polymorphisms increased the risk of urinary cancers, while others failed to replicate the association between the two. The inconsistent results may largely derive from small sample size, different designed methods and complex genetic backgrounds. In our study, we conducted meta-analysis to get conclusions of higher statistical power. To our best knowledge, this is the first meta-analysis evaluating the association between HIF1A P582S and A588T polymorphisms and the susceptibility of urinary cancers. On the other hand, there were some limitations similar to other meta-analyses which might affected the final results of our study. We performed a systematic search to find as complete published case-control studies as possible. However, a few studies would not have been included in the meta-analysis. Also, the number of eligible studies as well as included cases and controls for some analyses was not large enough. Thereby, we were actually underpowered to get significant associations. Moreover, our final results were based on unadjusted estimates. A more precise analysis stratified by age, different gender, lifestyle, and stages/grades of cancers should be conducted as individual studies were available.In the present study, we provide preliminarily genetic evidence that HIF1A P582S polymorphism is a potential factor for the susceptibility of urinary cancers in Caucasian population, while A588T polymorphism contributes to the risk of urinary cancers in Asian population and prostate cancer. Due to existing limitations, our conclusions should be interpreted with caution. Additional well-designed studies with larger sample size focusing on gene-gene and gene-environment are required to present robust evidence for the associations. Still, further molecular studies are warranted to clarify the effects of HIF1A P582S and A588T polymorphisms on the onset and progression of urinary cancers.


Recent studies on the association between miR-146a rs2910164 polymorphism and risk of gastrointestinal (GI) cancers showed inconclusive results. Accordingly, we conducted a comprehensive literature search and a meta-analysis to clarify the association.P = 0.14; GG+GC versus CC: OR = 1.14, 95%CI 1.00−1.31, P = 0.05; GG versus GC+CC: OR = 1.06, 95%CI 0.91−1.23, P = 0.47; GG versus CC: OR = 1.17, 95%CI 0.95−1.44, P = 0.13; GC versus CC: OR = 1.14, 95%CI 1.00−1.31, P = 0.05). Similar results were found in the subgroup analyses by ethnicity, cancer types, and quality of studies.Data were collected from the following electronic databases: Pubmed, Excerpta Medica Database (Embase), and Chinese Biomedical Literature Database (CBM), with the last report up to February 24, 2012. The odds ratio (OR) and its 95% confidence interval (95%CI) were used to assess the strength of association. Ultimately, a total of 12 studies  were found to be eligible for meta-analysis. We summarized the data on the association between miR-146a rs2910164 polymorphism and risk of GI cancers in the overall population, and performed subgroup analyses by ethnicity, cancer types, and quality of studies. In the overall analysis, there was no evidence of association between miR-146a rs2910164 polymorphism and the risk of GI cancers (G versus C: OR = 1.07, 95%CI 0.98−1.16, This meta-analysis demonstrates that miR-146a rs2910164 polymorphism is not associated with GI cancers susceptibility. More well-designed studies based on larger sample sizes and homogeneous cancer patients are needed. MicroRNAs (miRNAs) are small, non-coding, endogenous RNAs that represent a significant mechanism of post transcriptional gene regulation Primary miRNA transcripts are cleaved by Ribonuclease (RNase) III Drosha in the cell nucleus into 70-nucleotide to 80-nucleotide precursor miRNA (pre-miRNA) hairpins and transported to the cytoplasm. Then, pre-miRNAs are processed by RNase III Dicer into miRNA: miRNA duplexes. One strand of these duplexes is generally degraded, whereas the other is used as mature miRNA. Mature miRNAs can recognize and bind into the 3′-untranslated region (UTR) of the target mRNAs and interfere with their translation In the human genome, miR-146a is located at chromosome 5q33. Many recent studies have suggested that miR-146a expression is deregulated in many solid tumors The GI cancers share a number of characteristics that suggest common etiological pathways or mechanisms. Thus, the identification of possible risk factors and carcinogenetic mechanisms is essential for the prevention of these cancers. Accumulating evidence has uncovered the important role of inflammatory network in the promotion of GI cancer development We performed a systematic search using Pubmed, Excerpta Medica Database (Embase) and Chinese Biomedical Literature Database (CBM) with the last search updated on February 24, 2012. The following search terms were used: “microRNA OR mir OR miRNA”, “cancer OR carcinoma OR adenocarcinoma OR neoplasm OR tumour OR tumor”, “gene OR polymorphism OR allele OR variation”, and “146a OR rs2910164”. Searching was done without restriction on language or publication years. We evaluated all associated publications to retrieve the most eligible literature. Their reference lists were searched manually to identify additional eligible studies.The following inclusion criteria were used in selecting literature for further meta-analysis: (1) evaluation of miR-146a rs2910164 polymorphism and GI cancers; (2) independent case-control studies for human; (3) describing useful genotype frequencies; (4) only full-text manuscripts were included. Exclusion criteria included: (1) duplication of the previous publications; (2) abstract, comment, review and editorial; (3) family-based studies of pedigrees with several affected cases per family. When a study reported the results on different ethnicities, we treated them as separate studies. When there were multiple publications from the same population, only the largest study was included.Two investigators independently extracted the data according to the inclusion criteria listed above. Discrepancies were adjudicated by a third investigator until consensus was achieved on every item. The following information was extracted from each eligible study using a standardized data collection protocol /Q We used the PRISMA checklist as protocol of the meta-analysis and followed the guideline  [36]. WeP<0.05 was considered significant) by visual inspection of the funnel plot http://www.cc-ims.net/RevMan/relnotes.htm/) and Stata version 10 . The pooled ORs were performed for allelic comparison, dominant model, recessive model, homozygote comparison and heterozygote comparison, respectively. Thus, the Bonferroni method was used to adjust the significance alpha level to correct for the problem of multiple comparisons. Specifically, the usual significance level (α = 0.05) was divided by 5 to account for five comparisons. Thus, a P value less than 0.01 was considered statistically significant in the study, and all the P values were two sided.Potential publication bias was estimated using Egger’s linear regression test .Overall, when all types of GI cancers were considered together in the meta-analysis, there was no evidence of association between miR-146a rs2910164 polymorphism and the risk of GI cancers in any genetic model . In Caucasians, there was no evidence of association between the variant genotypes of miR-146a rs2910164 polymorphism and the risk of GI cancers in the allelic comparison .Next, we performed subgroup analyses according to ethnicity of the studies. In Asians, no significant association between miR-146a rs2910164 polymorphism and the risk of GI cancers was found for all genetic model , gastric cancer  and esophageal cancer .Moreover, we investigated the effect of the miR-146a rs2910164 polymorphism on the susceptibility to subtypes of GI cancers. No evidence of association was observed in any genetic model between miR-146a rs2910164 polymorphism and risk of liver cancer . In the subgroup of low quality studies, there was also no evidence of association between miR-146a rs2910164 polymorphism and the risk of GI cancers in any genetic model .We also performed subgroup analysis according to quality of studies. In the subgroup of high quality studies, no significant association between miR-146a rs2910164 polymorphism and risk of GI cancers was observed . However, Egger’s test was not applied in some comparisons due to the small number of studies.The results of Egger’s linear regression test are shown in In the present meta-analysis with 4,817 cases and 5,389 controls, there was no evidence of association between miR-146a rs2910164 polymorphism and the risk of GI cancers. Similar results were found in the subgroup analyses by ethnicity, cancer types, and quality of studies. The current study is the largest meta-analysis of the association between miR-146a rs2910164 polymorphism and the risk of GI cancers.P = 0.02) In 2011, several meta-analyses were conducted to investigate the association between miR-146a rs2910164 polymorphism and overall cancer risk. Xu et al. The current meta-analysis is based on a single polymorphism strategy to explore the association between miR-146a gene polymorphism and GI cancers. Duan and colleagues have identified 323 SNPs in 227 human known miRNAs Certain potential limitations exist in our meta-analysis. Firstly, the controls for one study included in this meta-analysis were not in Hardy-Weinberg equilibrium. To some extent, the results of genetic association studies might be distorted. Secondly, publication bias was detected in the subgroup analysis of gastric cancer for allelic contrast. This may also distort the meta-analysis. Thirdly, as with most meta-analyses, results should be interpreted with caution because of obvious between-study heterogeneity in some comparisons. Fourthly, if individual data were available, we could perform a more precise analysis with an adjustment estimate. Finally, colorectal cancer is the commonest cancer of the alimentary tract. Lacking sufficient eligible studies on colorectal cancer limited our further stratified analyses.In conclusion, results from meta-analysis of published data show that miR-146a rs2910164 polymorphism is not associated with GI cancers susceptibility. It is necessary to conduct more well-designed studies based on larger sample sizes and homogeneous cancer patients.Table S1Checklist of items to include in this meta-analysis.(DOC)Click here for additional data file.


FTO) is associated with risk of obesity in Europeans and Asians. Since obesity is associated with an increased risk of cardiovascular disease (CVD), several studies have investigated the association between variant in the FTO gene and CVD risk, with inconsistent results. In this study, we performed a meta-analysis to clarify the association of rs9939609 variant (or its proxies [r2>0.90]) in the FTO gene with CVD risk.Genome-wide association studies have shown that variance in the fat mass- and obesity- associated gene , and there was an insignificant change after adjustment for body mass index (BMI) and other conventional CVD risk factors .A total of 10 studies  were included in the meta-analysis. The results indicated that the rs9939609 variant was significantly associated with CVD risk (odds ratio = 1.18, 95% confidence interval = 1.07–1.30, FTO gene with CVD risk, which was independent of BMI and other conventional CVD risk factors.The present meta-analysis confirmed the significant association of the rs9939609 variant in the  FTO) associated with higher body mass index (BMI) and risk of obesity in the Europeans FTO gene variant affected T2D through an association with BMI/obesity FTO gene variant was associated with risk of T2D independently of BMI FTO gene, as the BMI/obesity related locus, might confer the risk on CVD. To date, nine papers have investigated the association between variance in FTO gene and CVD risk The prevalence of obesity has greatly increased globally FTO gene rs9939609 variant (or its proxies [r2>0.90]) Meta-analysis is a useful method to overcome the disadvantages of individual studies, thereby increasing the statistical power and the precision of effect estimates. In this study, we performed a meta-analysis to clarify the association between FTO) and (polymorphism or variant or variation or genotype) and . The publication language was restricted to English. The reference lists of retrieved articles were hand-searched. The literature search was updated on 31 December 2012.We searched literature databases, including PubMed and Embase. The search strategy was to identify all possible studies involving the following key words: (fat-mass and obesity-associated gene or FTO rs9939609 polymorphism (or its proxies [r2>0.90]) with risk of CVD; (2) use of a case–control or cohort design; and (3) provision of an odds ratio (OR) with 95% confidence interval (CI) under an additive model with or without adjustment for BMI and other conventional CVD risk factors . The following information was extracted from each study: (1) name of the first author; (2) year of publication; (3) country of origin; (4) ethnicity of the studied population; (5) number of cases and controls; (6) endpoint; (7) frequency of men and the mean ages; (8) mean BMI; and (9) studied SNP. Two authors independently reviewed the articles for compliance with the inclusion/exclusion criteria, resolved disagreements and reached a consistent decision. All participants of the included studies provided informed consent and the studies were approved by the ethics committees of the participating institutions.The studies were included in the meta-analysis only if they met all the following inclusion criteria: (1) evaluation of the association of FTO polymorphism with CVD was estimated by calculating the pooled OR and 95% CI. The significance of the OR was determined by the Z test . Cochrane’s Q test was performed to test the between-study heterogeneity I2 represents the range for the existence or no of heterogeneity. Usually, I2>50% represents the existence of heterogeneity. A random-effects (DerSimonian–Laird p≤0.10) or absence (p>0.10) of heterogeneity, respectively. To evaluate the stability of the results, we performed a sensitivity analysis by removing one study at a time. Publication bias was assessed by Begg’s test p<0.05 was considered statistically significant). Data were analysed using STATA version 11.0 .The association of FTO polymorphism and risk factors for CVD, e.g., obesity, hypertension, diabetes and insulin resistance r2>0.90). A total of 10 studies  for rs9939609 polymorphism (or its proxies) were included in the meta-analysis p>0.05). All studies . Galbraith figure was drawn to identify outliers of the source of heterogeneity. In the model unadjusted for BMI, four studies Meta-regress was conducted to examine the source of heterogeneity. Publication year, country, design, number of cases and controls were considered as independent variables. However, these variables can’t explain the source of heterogeneity  to 1.23   , and fro9, 1.39) .p = 0.118, p = 0.152, No publication bias was observed for the association between rs9939609 polymorphism and CVD risk without , although the association disappeared after adjustment for BMI FTO variant is associated with increased risk for hypertension through the regulation of sympathetic modulation of vasomotor tone FTO variant could increase the risk of CVD through another mechanism, namely through its possible effect on DNA methylation. In other words, the FTO gene variant could interact with an unhealthy lifestyle , and affect the epigenetic status The mechanism underlying the association of the FTO gene variant and CVD risk.Our study is subject to several limitations. First, the individual studies are not homogeneous in the subject cases that might have an effect in the meta-analysis . Only fiFTO gene rs9939609 variant is significantly associated with an increased risk of CVD in the Europeans and the genetic effect is not mediated by the changes in BMI and other conventional CVD risk factors. The observed association remains to be replicated in the non-European populations. Further studies should be conducted to investigate the mechanism underlying the link between FTO gene and CVD risk.In conclusion, our meta-analysis confirmed that the Figure S1Galbraith figure for identification outliers of the source of heterogeneity in the model unadjusted for BMI.(TIF)Click here for additional data file.Figure S2Galbraith figure for identification outliers of the source of heterogeneity in the model adjusted for BMI.(TIF)Click here for additional data file.Figure S3Funnel plot for the association between rs9939609 polymorphism and CVD risk without adjustment for BMI.(TIF)Click here for additional data file.Figure S4Funnel plot for the association between rs9939609 polymorphism and CVD risk with adjustment for BMI.(TIF)Click here for additional data file.Table S1(DOC)Click here for additional data file.Table S2(DOC)Click here for additional data file.


Age-related macular degeneration (AMD) is an ocular disease affecting macula — the central part of the retina, resulting in the degeneration of photoreceptors and retinal epithelium and causing severe central vision impairment. The pathophysiology of the disease is not completely known, but a significant role is attributed to genetic factors. The contribution of oxidative stress in AMD as a trigger of the degenerative process is well-established. Iron ions may act as a source of reactive oxygen species; therefore, maintaining iron homeostasis is important for redox balance in the organism. Diversity in iron homeostasis genes may counterpart in unbalanced redox state, and thus be involved in AMD pathophysiology.In this work, we searched for an association between some single nucleotide polymorphisms in the divalent metal transporter 1 (DMT1) gene intronic IVS4+44C>A (rs224589) and 3’-UTR c.2044T>C (rs2285230) and environmental factors and AMD. Genotyping was performed using the PCR-RFLP method. DNA was obtained from 436 AMD patients and 168 controls.We did not find any association between the genotypes of the two polymorphisms and AMD occurrence. However, we observed that AMD patients living in a rural environment and having the CC genotype of the IVS4+44C>A polymorphism had an increased risk of AMD, while individuals with the CA genotype or the A allele had a decreased risk of the disease. Moreover, in male AMD patients the C allele increased the risk of the disease, while the AA genotype decreased it.These results suggest that the VS4+44C>A polymorphism of the DMT1 gene may interact with place of living and gender to modulate the risk of AMD. Age-related macular degeneration (AMD) is the primary cause of irreversible vision loss among the elderly, in developed countries . AMD is AMD is a progressive disease, developing in its late stage to one of two clinically distinct forms — dry or wet . The dryThe etiology of AMD is complex, and the mechanism of retinal cell death has not been fully understood. The eye is constantly exposed to short-wavelength light . That caThe level of oxidative imbalance in the cell may exceed its oxidative defense capacity. Then it can cause oxidative damage to different cellular components including DNA, promoting apoptosis , 27. It Genetic factors are considered to play an important role in AMD, as has been shown in a number of family and twin studies . SeveralThis study included a group of 436 individuals — 290 with the wet form of AMD, 148 with the dry form of the disease, and 168 controls. Medical history was obtained from all subjects, and no one reported any genetic disease. The patients underwent ophthalmic examination, including best-corrected visual acuity, intraocular pressure, slit-lamp examination, and fundus examination, performed with a slit lamp equipped with either non-contact or contact fundus lenses. The criteria for enrolling patients into the study groups were based primarily on clinical usefulness; the dry form group corresponded to AREDS categories 2, 3 and 4 (geographic atrophy subtype) and the wet to AREDS category 4  . DiagnosThe sample of whole venous blood was collected from every subject to EDTA-containing tubes. DNA was isolated from each sample using AxyPrep Blood Genomic DNA Miniprep kit  and stored deep frozen (−20°C) until use.2 and 0.25 μM of each primer . The sequence of primers for the IVS4+44C>A polymorphism was as in reference [TM thermocycler  Thermal cycling conditions for the IVS4+44C>A polymorphism were: initial denaturation step at at 95°C for 3 min, 34 cycles of denaturation at 95°C for 30 s, annealing at 60°C for 30 s and amplification at 72°C for 1 min; final extension at 72°C for 5 min. For the c.2044T>C polymorphism, these conditions were: initial denaturation step at 95°C for 5 min, 33 cycles of denaturation at 95°C for 30 s, annealing at 62°C for 30 s and amplification at 72°C for 1 min; final extension at 72°C for 5 min.Each reaction tube contained 10 ng of genomic DNA, 0.75U Taq Polymerase , 1 × reaction buffer, 0.5 mM dNTP, 1.5 mM MgCleference . The seqAmplified DNA fragment containing IVS4+44C/A site was incubated with 1.5 U of MnlI restriction enzyme  for 4 h at 37°C, while fragment containing the c.2044T>C site was incubated with 1.5U of RsaI restrictase  for 2.5 h in 37°C. The length of digestion products is shown in Table After digestion samples were separated on 10% polyacrylamide gel, electrophoresis was run at 5 V/cm in BLUESTAR apparatus  in Tris-borate–EDTA buffer. ΦX-174 DNA/BsuRI (HaeIII) DNA ladder was utilized as a mass marker. After separation, gels were stained with ethidium bromide (0.5 μg/ml) and documented by the digital imaging system InGenius Bio Imaging . Representative gels for genotyping the IVS4+44C/A and c.2044T>C polymorphism are shown in Figs. 2 analysis. Unconditional logistic regression analysis was performed to assess the association between the genotypes of the polymorphisms and AMD incidence. The genotype-associated risk was expressed by crude odds ratio with 95% confidence intervals and the p value. Odds ratios were then adjusted for possible interfering factors. To verify a potential gene–environment interaction, the patients and controls were stratified depending on age, sex, living environment , smoking status and body mass index (BMI). Multiple unconditioned logistic regression analyses were run to test the association of genotypes and environmental and social factors with AMD occurrence. Statistical analysis was performed using the Statistica 9.0 package .The allelic frequencies were calculated by gene counting, and genotypes were scored. The significance of the differences between distributions of genotypes and alleles was tested using the χp > 0.05 for each group. The patient characteristics contained information about environmental and social factors having possible impact on AMD incidence. The analysis of the association between potential risk factors — age, sex, inhabitation, smoking habit, and Body Mass Index and AMD independently from genotypes was performed  and the occurrence of the disease among 1st-degree relatives . The next step was to test the association between the genotypes of both polymorphisms and AMD. No association was found between the risk of AMD and the genotypes of that polymorphism in the group of all AMD patients (dry and wet forms) (Table p < 0.05), and the CA genotype and the A allele was inversely correlated with AMD  in the group of rural inhabitants (Table p < 0.05), while the C allele had a strong positive linkage with AMD among males  (Table The frequencies of genotypes in the groups did not differ significantly from Hardy-Weinberg equilibrium — ed Table . We founs) Table  or dry  in the 3’UTR region , 50. The protein , 58. Thi protein  and here protein , but its protein . We did Our genotype-independent analysis of potential AMD risk factors showed an association with age and a strong association with familial AMD. Therefore, positive AMD familial history may increase the risk of the occurrence of the disease among remaining family members. On the other hand, we found no association of AMD with smoking status, sex, BMI, and place of living. In particular, the lack of association of AMD with sex and smoking is somehow surprising, because several groups have shown a significant association between tobacco smoking and AMD . Further


Epidermal growth factor (EGF), a potent mitogenic protein, plays an important role in the development of cancers, including glioma. Previous studies showed that the EGF +61G/A polymorphism (rs4444903) may lead to an alteration in EGF production and/or activity, which can result in individual susceptibility to glioma. However, published data regarding the association between the +61G/A polymorphism and glioma risk was contradictory.The aim of this study was to perform a meta-analysis of eligible studies to derive precise estimation of the association of EGF +61G/A with glioma risk.We performed a pooled analysis of seven published studies that included 1,613 glioma cases and 2,267 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. The pooled ORs were performed for codominant model, dominant model, and recessive model, respectively.Overall, no significant associations between the EGF +61G/A polymorphism and glioma cancer risk were found for AA versus GG , GA versus GG , AA/GA versus GG , and AA versus GA/GG . However, in the stratified analysis by ethnicity, the EGF +61G/A polymorphism had a higher risk of glioma development among Asians, but a lower risk among Caucasians.Taken together, the results suggest that the EGF +61G/A polymorphism may contribute to the susceptibility of glioma in different ethnic groups. Gliomas are the most common type of primary brain tumors, which accounts for more than 40% of the newly diagnosed brain tumors The epidermal growth factor (EGF) gene is located in chromosome 4q25-27. It is a member of the EGF superfamily, which includes transforming growth factor-α, heparin-binding EGF-like growth factor, epiregulin, betacellulin, and amphiregulin To date, a number of studies have reported the association between the EGF +61G/A polymorphism and glioma risk, but the results were inconclusive. Two published articles tried to find this association by performing meta-analysis One online electronic database (PubMed) was searched using the search terms ‘epidermal growth factor’ or ‘EGF’, ‘polymorphism’, and ‘glioma’, ‘genetic susceptibility’, single nucleotide polymorphisms, ‘germline variation’ . The search was limited to English-language papers. Additional studies were identified by a hand search of the references of original studies. Of the studies with the same or overlapping data published by the same investigators, we selected the most recent ones with the largest number of subjects.The inclusion criteria were (a) on EGF +61G/A polymorphism and glioma risk, (b) case-control studies, and (c) containing useful genotype frequencies. Major exclusion criteria were (a) no control population, (b) no available genotype frequency, and (c) duplication of the previous publication.Information was carefully extracted from all eligible publications independently by two investigators according to the inclusion criteria listed above. When it came to conflicting evaluations, an agreement was reached after a discussion. For each study, the following data were considered: the first author's last name, year of publication, country of origin, ethnicity, exposure to high-dose ionizing radiation, and numbers of genotyped cases and controls. Different ethnic descents were categorized as Caucasian and Asian. We did not define any minimum number of patients to include a study in our meta-analysis.P>0.05 of the Q-test which indicates a lack of heterogeneity among studies, the summary OR estimate of each study was calculated by the fixed-effects model (the Mantel-Haenszel method) P<0.05, statistically significant publication bias existed The strength of association between the EGF +61G/A polymorphism and glioma risk was assessed by calculating crude odds ratios (ORs) with 95% confidence intervals (CIs). The pooled ORs were performed for codominant model , dominant model (AA/GA versus GG), and recessive model (AA versus GA/GG), respectively. Stratified analyses were also performed by ethnicity and sources of controls. In consideration of the possibility of heterogeneity across the studies, a statistical test for heterogeneity was performed based on the Q statistic A total of seven eligible studies involving 1,613 cases and 2,267 controls were included in the pooled analyses As shown in P = 0.012 for AA/GA versus GG).There were significant heterogeneity between studies in overall comparisons . A singlThis meta-analysis examined all the available data on the association between the EGF +61G/A polymorphism and glioma risk, including a total of 1,613 glioma cases and 2,267 controls. We found that the variant genotypes of the +61G/A polymorphism were associated with significant increased risk of glioma among Asians, and decreased risk among Caucasians. Given the important roles of EGF in cell proliferation, differentiation or survival through binding to EGFR, it is biologically plausible that EGF polymorphism may modulate the risk of glioma.in vitro and decreased risk of malignant melanoma Genetic variants occurred in EGF promoter region may influence gene expression, dysregulate EGF signaling, and lead to neoplastic transformation Our results showed that the EGF +61G/A polymorphism had a significant increased risk of glioma in Asians, but decreased risk in Caucasians, suggesting a possible role of ethnic differences in genetic backgrounds and the environment they live in Recently, in order to identify common, low-penetrance cancer susceptibility genes, large genome-wide association studies (GWAS) have been performed, including glioma. GWAS of glioma in populations of European ancestry were completed in the United States and the United Kingdom Some limitations of this meta-analysis should be addressed. First, the eligible studies were only published studies included in the meta-analysis; therefore, publication bias have occurred in our study. Second, the subgroup used for meta-analysis for interactions between EGF polymorphism and cigarette smoking did not include all eligible studies, because it was not possible to obtain information from some studies on smoking status. Third, meta-analysis remains retrospective research that is subject to methodological deficiencies. Despite these limitations, a detailed protocol initiating the analysis was included, by performing standardized methods for study selection, data extraction, and data analysis.Our meta-analysis suggested that the EGF +61G/A polymorphism may be associated with an increased glioma risk among Asians, but a decreased glioma risk among Caucasians. However, in the stratification by source of controls, no significant association was found with respect to glioma risk in the EGF +61G/A polymorphism. Larger and well-designed multicentric studies based on the same ethnic group and other cancers are warranted to validate our findings.


NQO1 gene, a 609C>T substitution, leading to proline-to-serine amino-acid and enzyme activity changes, has been implicated in cancer risk, but individually published studies showed inconclusive results.The functional polymorphism (rs1800566) in the NQO1 609C>T polymorphism and risk of GI cancers and performed subgroup analyses by ethnicity, cancer site, and study quality. We found that the variant CT heterozygous and CT/TT genotypes of the NQO1 609 C>T polymorphism were associated with a modestly increased risk of GI cancers . Following further stratified analyses, the increased risk was only observed in subgroups of Caucasians, colorectal cancer in Caucasians, and high quality studies.We performed a meta-analysis of 20 publications with a total of 5,491 cases and 5,917 controls, mainly on gastrointestinal (GI) cancers. We summarized the data on the association between the NQO1 609T allele is a low-penetrance risk factor for GI cancers. Although the effect on GI cancers may be modified by ethnicity and cancer sites, small sample seizes of the subgroup analyses suggest that further larger studies are needed, especially for non-colorectal GI cancers in Caucasians and GI cancers in Asians.This meta-analysis suggests that the  Gastrointestinal (GI) cancers are the common malignant tumors in the world in vivo and in vitro studies have demonstrated that NQO1 regulates the stability of the tumor suppressors p53 and p73, protecting them from 20S proteasomal degradation, which is important for eliminating damaged cells that are prone to cancer development NAD(P)H:quinone oxidoreductase 1 (NQO1) is an obligate two-electron reductase, which reduces reactive quinones to less reactive and less toxic hydroquinones. The quinones are mainly derived from endogenous quinones, such as vitamin E quinone and ubiquinone, and exogenous quinones, such as exhaust gas, cigarette smoke or diet NQO1 gene is located on chromosome 16q22.1, spanning ∼17.2 kb and consisting of 6 exons and 5 introns NQO1 gene (http://www.ncbi.nlm.nih.gov/SNP). The most extensively studied SNP of NQO1 is a C-to-T transition at nucleotide position 609 in exon 6  having the lowest, the heterozygotes (CT) having the intermediate, and the wild-type homozygotes (CC) having the highest NQO1 enzyme activity NQO1 609C>T polymorphism was associated with reduced NQO1 protein expression in tumor tissues from a subset of GI cancer patients  NQO1 609C>T polymorphism on risk of GI cancers, including cancers of the esophagus, stomach, colorectum, pancreas, and liver. However, the reported genetic effects varied across the published studies, and a clear impact of this SNP on cancer risk is also limited by the insufficient statistical power of these individual studies with a relatively small sample size. Therefore, we performed a meta-analysis of published data to evaluate the influence of the NQO1 609C>T polymorphism on the risk of GI cancers.The NQO1 609C>T polymorphism (rs1800566) with the risk of GI cancers , which had been published up to October 6, 2011 with a limit to human studies in English language. The following keywords were used: ‘NAD(P)H Dehydrogenase (Quinone)’ or ‘NQO1’, ‘polymorphism’, ‘variant’, and in combination with ‘gastrointestinal/aerodigestive tract cancers’, or ‘esophageal cancer’, ‘gastric/stomach’ cancer, ‘colorectal/colon/rectum cancer’, ‘ pancreatic cancer’, ‘liver cancer’, ‘hepatocellular carcinoma’, ‘gallbladder cancer’, and ‘small/larger bowel cancer’. In addition, the references cited in the retrieved studies were also reviewed manually to identify publications on the same cancer type. If studies from the same study group had overlapped subjects, the most recent or largest study was included in the final analysis. Human population-based or hospital-based association studies were included in this meta-analysis, if they met all the following criteria: (1) an independent, unrelated case-control, nested case-control, or cohort study, (2) the NQO1 609C>T polymorphism was determined, (3) the outcome was GI cancers, (4) there were sufficient data for calculating an odds ratio (OR) with 95% confidence interval (CI), and (5) the study was reported in English. Exclusion criteria were: (1) duplicate data, (2) abstract, case report, comment, review and editorial, (3) no sufficient genotyping data were provided, (4) the outcome was benign tumors, precancerous lesions, and adenomas, and (5) family-based study.Using the PubMed search engine, we searched Medline databases, on the association of Two reviewers (HY and HL) independently reviewed the articles and extracted the data from all eligible publications according to the criteria listed above. The following information was recorded for each study: first author, year of publication, country or region of origin, ethnicity, cancer type, number of cases and controls, number of cases and controls by genotype, source of control group , genotyping methods, minor allele frequency in controls, method for matching controls to cases. Any discrepancies between the two investigators were resolved by discussion and consultation with a third reviewer (LW). and the scores were defined as 1 to 3 points given to each component or 0 if absent or the study with a sample size of less than 200. A final quality score was obtained by summation of each component giving a range from 0 (the lowest) to 15 (the highest). Studies scoring<8 were classified as low quality, and those ≥8 as high quality. Disagreements were resolved by consultation with the third reviewer.The quality of included studies was independently assessed by the same two reviewers using the quality assessment criteria, which was modified from previously published meta-analysis of molecular association studies NQO1 609C>T polymorphism in control subjects from Hardy-Weinberg equilibrium (HWE) was tested by using the Chi-square goodness of fit, and a P value<0.05 was considered significant. Odds ratio (OR) and corresponding 95% confidence interval (95% CI) were used to estimate the association between the NQO1 609C>T polymorphism and cancer risk. We estimated the risk for the variant homozygous TT and heterogeneous CT genotypes, compared with the wild-type homozygous CC genotype, and then for CT/TT vs. CC and TT vs. CC/CT, assuming both dominant and recessive effect models, respectively. The heterogeneity across studies was assessed with the Q test, and the heterogeneity was considered significant when a P-value<0.1 for the Q statistic I2 index, which can quantify the degree of heterogeneity in a the meta-analysis P-value<0.1 was used as an indication for the presence of potential publication bias. Sensitivity analyses were conducted by including and excluding studies not in HWE, and by removing one study at a time to assess the influence of individual studies on the pooled ORs, respectively. All analyses were performed by using Review Manager  and Stata software . In addition, for each statistically significant association, we estimated the false positive report probability (FPRP) using the method described by Wacholder et al P-value Deviation of genotype frequencies of the NQO1 609C>T polymorphism and risk of GI cancers. After retrieving the full text of these 29 articles, we excluded 9 articles because of the following reasons: one reported the association between the NQO1 609C>T SNP and H. pylori seropositivity NQO1 609C>T but on NQO1 R139W SNP (rs4986998) NQO1 609C>T SNP and colorectal adenoma NQO1 609C>T genotypes and NQO1 activity As of October 6, 2011, we had identified 29 potentially eligible studies that have investigated the association between the NQO1 609C>T polymorphism in controls in 19 of 20 included studies were in agreement with HWE. The HWE test in the study by Lafuente et al. was not mentioned vs. CT/CC) was available. Therefore, this study was included in the analysis for the recessive model but not for other genetic models. Quality scores for the individual studies ranged from 4 to 13, with 60.0% (12 of 20) of the studies being classified as high quality (≥8).Overall, data from 20 publications with 5,491 cases and 5,917 controls were available for our meta-analysis. Main characteristics of the included publications are presented in NQO1 609 C>T polymorphism were different between these two ethnic groups. The frequencies of the TT, CT, and CC genotypes were 3.1%, 28.2%, and 68.7%, respectively, in Caucasians and 13.1%, 44.7%, and 42.2% in Asians, respectively . A main effect also was significant in the dominant model  . We found similar effects in the homozygous comparison  and in the recessive model comparison . However, these effects did not reach statistical significance. A modest heterogeneity among the studies was observed . Subsequent sensitivity analyses were performed by removing the individual study sequentially, and we found that all but one Japanese study by Hamajima et al. vs.CC: OR = 1.27, 95% CI: 1.03 – 1.47) or in the recessive model comparison , and the heterogeneity among the studies was not significant , suggesting that this study may contribute to the observed heterogeneity across studies.Overall, as shown in  – 1.20) Figure 3vs. CC: OR = 1.13, 95% CI: 1.01 –1.26, Pheterogeneity = 0.24 and and 2I = 0.22) and the dominant model comparison , but not in the homozygous genotype comparison  and the recessive model comparison . No significant heterogeneity was observed for all the genetic mode1 comparisons. The leave-one-out sensitivity analysis found that no single study dramatically influenced the overall pooled ORs (data not shown). In Asians, no significant association between the NQO1 609C>T polymorphism and the risk of GI cancers was found for all variant genotypes , the dominant model  and the recessive model . However, the leave-one-out sensitivity analysis showed that after removing the study by Hamajima et al. vs.CT/CC: OR = 1.36, 95% CI: 1.02 – 1.81, Pheterogeneity = 0.23 and 2I = 0.26). In further stratification analysis by cancer site . However, no significant association was observed for other cancer sites either in Caucasians or in Asians. The leave-one-out sensitivity analysis showed that no single study dramatically influenced the overall pooled ORs (data not shown).In the stratified analysis by ethnicity, as shown in vs.CC: OR = 1.10, 95% CI: 1.00 – 1.22; Pheterogeneity = 0.27 and 2I = 0.18), and such an effect was also found in the dominant genetic model . Similar effects were also found for the homozygous genotype comparison  and for the recessive genetic model comparison , though they did not reach statistical significance. In the subgroup of low quality studies, no significant association between the NQO1 609C>T polymorphism and the risk of GI cancers was observed. Sensitivity analyses showed that no single study influenced quantitatively the overall pooled ORs (data not shown).We also performed subgroup analysis by quality score of studies Table 3.Q test and the 2I index to evaluate the heterogeneity across studies. As shown in Q test showed that there was no significant heterogeneity in some overall comparisons and subgroup analyses, the 2I index suggested that a low to high heterogeneity across studies presented in most of comparisons. We assessed heterogeneity across studies by ethnicity, cancer site, and quality of studies, and found that they did not contribute the heterogeneity observed across the studies in the overall meta-analysis . These factors were also not found to contribute to the heterogeneity across studies in some of the subgroup analysis (data not shown). Together with the results from the leave-one-out sensitivity analysis as mentioned above, the study by Hamajima et al. could be the main source of the observed heterogeneity across the studies in this meta-analysis.In the present study, we used the vs.CC: PBegg = 0.529 and PEgger = 0.369, TT vs.CC: PBegg = 0.726 and PEgger = 0.690, CT/TT vs.CC: PBegg = 1.000 and PEgger = 0.671, and TT vs.CT/CC: PBegg = 0.626 and PEgger = 0.700.) Neither funnel plots nor Begg's and Egger's tests detected any obvious evidence of publication bias in the subgroup analyses for all genetic models (data not shown).Both Begg's and Egger's tests were performed to evaluate the publication bias of the included studies. The shape of the funnel plots did not reveal any evidence of obvious asymmetry for all genetic models in the overall meta-analysis Figure 4NQO1 609C>T polymorphism and risk of GI cancers.Finally, because many subgroup comparisons were conducted, we calculated false positive report probability (FPRP) for each statistically significant result. As shown in NQO1 609 C>T polymorphism was found to be associated with a modestly increased risk of GI cancers, and no significant heterogeneity was found across studies. It was also noted that, when limiting the pooled analysis to the studies with high quality, the results were persistent and robust, with the NQO1 609 T allele being significantly associated with the increased risk of GI cancers. Publication bias was not observed in this study. These findings suggest that the NQO1 609C>T polymorphism may modify the risk of GI cancers.In the present meta-analysis with 5,491 cases and 5,917 controls, the variant CT heterozygous genotype and the combined CT/TT genotype of the NQO1 knockout mice were reported to exhibit marked increased sensitivity to 7,12-dimethylbenz(a)anthracene (DMBA)- and benzo(a)pyrene (BP)-induced skin carcinogenesis Our findings have some biological plausibility, because NQO1 performs multiple functions within the cell. Conclusive evidence suggests that NQO1 has a protective function in cellular defense against the toxicity of electrophilic and oxidizing metabolites of xenobiotic quinones NQO1 is polymorphic NQO1 609C>T polymorphism, in terms of its frequency and phenotypic consequences, is most prominent and thus intensively studied. Our results are consistent with the potentially altered biological functions of NQO1 by the 609C>T polymorphism. Although the association of the homozygous variant genotype (TT) with overall cancer risk did not achieve statistical significance, the magnitude and direction for association for GI cancers were persistent in both overall and some subgroups in our meta-analysis. Because the frequency of the TT genotype of the NQO1 609C>T polymorphism was low in the published study populations, with 3.1% and 13.1% of the controls being the TT homozygote in Caucasians and Asians, respectively, we might not have sufficient statistical power to detect the weak effect of this variant genotype on risk of GI cancers. Further studies with larger sample sizes are warranted.Human H. Pylori infection is involved in stomach cancer and HBV/HCV infection is involved in liver cancer, while dietary exposure to heterocyclic amines (HCAs), nitrosamines, polycyclic aromatic hydrocarbons (PAHs) derived from red meat and processed meat is a key risk factor for colorectum cancer. Such etiologic heterogeneity in GI cancers raises the possibility that the NQO1 polymorphism may be associated with specific types of GI cancers, because NQO1 plays an important role in detoxifying dietary carcinogenic compounds such as HCAs, PAHs and nitrosamines NQO1 609 C>T polymorphism resulting in decreased activity of NQO1 enzyme may increase risk of colorectum cancer. Indeed, in the stratification analysis by cancer site in Caucasians and Asians, significantly elevated risk associated with the NQO1 609T allele was only found for colorectal cancer among Caucasians but not in Asians. A previous meta-analysis by Chao et al. NQO1 609T allele and an increased risk for colorectal cancer  among 1637 cases and 1854 controls in the Caucasian population, and this association remained statistically significant in this expanded meta-analysis that had included additional subjects (2410 cases and 2676 controls in the Caucasian population). However, the meta-analysis for the NQO1 609C>T polymorphism and colorectal cancer risk was not performed in Asian population in Chao's study. We also did not find significant associations between this SNP and risk of other cancer sites, such as cancers of the esophagus, stomach, and pancreas either in Caucasians or in Asians. This lack of significance could be due to either no effect of this SNP on these cancer sites or limited statistical power to detect such a weak association. In our meta-analysis, only two studies with 316 cases and 341 controls for pancreatic cancer in Caucasians, three studies with 375 cases and 1,000 controls for gastric cancer and three studies with 916 cases and 1577 controls for colorectum were conducted in Asians. Therefore, our results should be interpreted with caution. Because the NQO1 609C>T polymorphism is functional and potentially to be associated with risk of cancer as shown in this meta-analysis, further larger studies are needed, especially for non-colorectal GI cancers in Caucasians and GI cancers in Asians.GI cancers represent a heterogeneous group of malignancies. Except for some shared risk factors, different primary sites of GI cancers have different risk factors and thus different etiologies. For example, in addition to smoking and alcohol consumption, NQO1 609C>T polymorphism and risk of GI cancers, suggesting some possible bias in the findings. Finally, due to lacking individual original data, we did not take into account the other factors such as sex, ethnicity, smoking and drinking status, that could modify the risk of estimate NQO1 609 C>T polymorphism on the risk of GI cancers. A more precise analysis could have been conducted, if individual data were available. Furthermore, gene-environment and gene-gene interactions should also be considered in further studies.Certain potential limitations exist in our meta-analysis. Firstly, although the Begg's test and Egger's test did not show any publication bias, selection bias could have occurred, because only studies published in English were included in our meta-analysis. Secondly, all the studies included in this meta-analysis were hospital-based case-control studies. In this instance, the hospital-based controls may not be representative of the general population. Thirdly, the numbers of published studies were still not sufficiently large for the analysis of the effect of the variant TT genotype on risk of GI cancers and for some subgroups. Furthermore, we were unable to perform further subgroup analyses for a particular cancer site in different ethnic populations due to a limited number of published studies available to be included. For example, only one Caucasian study and one Asian study for gastric cancer and liver cancer were available for this meta-analysis, respectively. Fourthly, the FPRP analyses showed that with the assumption of a prior probability of 0.1, the FPRP values for the significant findings in overall comparisons and the comparison in the dominant model in Caucasians were below 0.2, providing some measures of robustness for our observations. However, greater FPRP values were observed for the other significant associations between the NQO1 609C>T polymorphism may be associated with a moderately increased risk of GI cancers. Although the effect on cancer risk may be modified by ethnicity and cancer sites, small sample sizes in some subgroups suggest that future large and well-designed studies in different ethnic populations and different sites of GI cancers are needed to validate our findings.In summary, despite the above-mentioned limitations, our meta-analysis suggests that the minor allele T of the Table S1Score of quality assessment.(DOC)Click here for additional data file.


The X-ray repair cross-complementing group 1 (XRCC1) protein plays a crucial role in base excision repair (BER) pathway by acting as a scaffold for other BER enzymes. Variants in the XRCC1 gene might alter protein structure or function or create alternatively spliced proteins which may influence BER efficiency and hence affect individual susceptibility to bladder cancer. Recent epidemiological studies have shown inconsistent associations between these polymorphisms and bladder cancer. To clarify the situation, a comprehensive meta-analysis of all available studies was performed in this study.PubMed, EMBASE, and Chinese Biomedical Literature database (CBM) databases have been systematically searched to identify all relevant studies for the period up to February 2013. Data were abstracted independently by two reviewers and Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Subgroup analyses were performed mainly by ethnicity and smoking status.P=0.015 and recessive model AA vs. GA+GG: OR=0.680, 95%CI= 0.515-0.898, P=0.007, respectively). With respect to R194W and R280H polymorphism, significantly increased bladder cancer risk were observed among Asians .A total of 26 case-control studies, including 24 studies for R399Q polymorphism, 15 studies for R194W polymorphism, and 7 studies for R280H polymorphism met the inclusion criteria and were selected. With respect to R399Q polymorphism, significantly decreased bladder cancer risk was found among smokers (AA vs. GG: OR=0.693, 95%CI= 0.515-0.932, This meta-analysis suggests that the XRCC1 R399Q polymorphism may play a protective role against bladder cancer among smokers. However, the XRCC1 R194W and R280H polymorphisms were both associated with increased bladder cancer risk among Asians. Further studies with larger sample sizes are needed to validate our finds. Bladder cancer is one of the most common cancers of the urinary tract and a major problem worldwide . The mai2 terminus, human AP endonuclease, polynucleotide kinase, and poly (ADP-ribose) polymerase, and via its function in recognizing and binding to single strand breaks [X-ray repair cross-complementing group 1 (XRCC1) is an essential DNA repair protein involved in BER pathway. The XRCC1 protein has no known catalytic activity but serves to orchestrate base excision repair via its role as a central scaffolding protein physically associated with DNA ligase III at its COOH terminus, DNA polymerase at its NHd breaks –9. ThereHuman XRCC1 gene maps to chromosome 19q13, 2 and is composed of 17 exons. It spans approximately 31.9kb, and encodes a protein of 633 amino acids. More than 300 validated single nucleotide polymorphisms (SNPs) in XRCC1 are listed in the dbSNP database, of which, approximately 35 variants are located in exons or promoter regions. The most extensively studied SNPs are R399Q on exon 10 , R194W on exon 6 , and R280H on exon 9 . These nonconservative amino acid alterations might influence DNA repair capability by altering the protein–protein interactions between XRCC1 and other BER proteins. Hence, it is biologically reasonable to hypothesize a potential relationship between XRCC1 polymorphisms and Bladder cancer risk. A study published in 2001 showed there was a protective effect for subjects that carried at least one copy of the codon 194 variant allele compared with those homozygous for the common allele  [This study was performed according to the proposal of Meta-analysis of Observational Studies in Epidemiology group (MOOSE) . We condStudies included in the meta-analysis were required to meet the following criteria: (1) Case–control studies which evaluated the association between XRCC1 polymorphisms and bladder cancer risk; (2) used an unrelated case–control design; (3) had an odds ratio (OR) with 95% confidence interval (CI) or other available data for estimating OR (95% CI); and (4) control population did not contain malignant tumor patients. Conference abstracts, case reports, editorials, review articles, and letters were excluded.Two separate investigators (Shan Li and Qiliu Peng) independently reviewed and extracted data from all eligible studies. Data extracted from eligible studies included the first author, year of publication, country of origin, ethnicity, genotyping method, matching criteria, source of control, bladder cancer confirmation, QC when genotyping, total numbers of cases and controls and genotype frequencies of cases and controls. Ethnic backgrounds were categorized as Caucasian, Asian, and African, and smoker status (smoker or nonsmoker) was additionally recorded for the stratified analysis. Smokers included current smokers and former smokers. Nonsmokers had never smoked. If a study did not state the ethnic descendent or if it was not possible to separate participants according to such phenotype, the group reported was termed as “mixed ethnicity”. To ensure the accuracy of the extracted information, the two investigators checked the data extraction results and reached consensus on all of the data extracted. If different results were generated, they would check the data again and have a discussion to come to an agreement. A third reviewer (Xue Qin) was invited to the discussion if disagreement still existed.Methodological quality was independently assessed by two reviewers (Shan Li and Qiliu Peng), according to a set of predefined criteria  based onp value of less than 0.05 was considered significant. We assessed the associations of XRCC1 R399Q polymorphism with bladder cancer risk using additive genetic models (AA vs. GG and GA vs. GG), recessive genetic model (AA vs. GA+GG), and dominant genetic model (AA+GA vs. GG). However, with respect to R194W and R280H polymorphisms, the associations were assessed only by using dominant genetic model  because of the low carrier rate of the mutate homozygote in the studied populations.The strength of the association between XRCC1 polymorphisms and bladder cancer risk was measured by odds ratios (ORs) with 95% confidence intervals (CIs). The significance of the pooled OR was determined by the Z test and a Q statistic test to test for heterogeneity and the I2 statistic to quantify the proportion of the total variation due to heterogeneity were calculated. Because of the low power of Cochran’s Q statistic, heterogeneity was considered significant when the results of the Q test was PQ < 0.1 or I2 ≥ 50%, and the random-effects model was used to pool the results. Otherwise, the fixed-effects model was used to pool the results when the result of the Q test was PQ ≥ 0.1 and I2 < 50%. Besides, the Galbraith plot was used to spot the outliers as the possible major sources of heterogeneity [Two models of meta-analysis for dichotomous outcomes were conducted in this study: the random-effects model and the fixed-effects model. The random-effects model was conducted using the DerSimonian and Laird’s method , which aogeneity . To bettp values were two-sided. To ensure the reliability and the accuracy of the results, two authors imported the data into the statistic software program independently and got the same results.Subgroup analyses were performed by ethnicity, smoking status, and studies in HWE. Publication bias was investigated by funnel plot, in which the standard error of logor of each study was plotted against its logor. An asymmetric plot suggested possible publication bias. In addition, funnel-plot asymmetry was assessed by the method of Egger’s linear regression test . The disWith our search criteria, 102 individual records were found initially. After screening the titles and abstracts, 63 were excluded  and only 39 full-text publications were preliminarily identified for further detailed evaluation . AccordiI2 =55.1%, PQ=0.002), thus, the random-effects model was used to pool the results. The results of pooling all studies showed that the R399Q polymorphism was not associated with bladder risk in all genetic models , thus the fixed-effects model was used to pool the results. The combined results showed that the R194W polymorphism was not associated with bladder cancer risk (P=0.006), while the association was also not found in Caucasians and Africans , thus the random-effects model was used to pool the results. The combined result showed that the R280H polymorphism was significantly associated with increased bladder cancer risk . In subgroup analyses by ethnicity, the results showed that the R280H polymorphism was associated with an increased bladder cancer risk among Asians , Asians , and studies in HWE . The signiﬁcance of the summary ORs for the R399Q polymorphism in different comparison models in the overall populations and subgroup analyses were not inﬂuenced by omitting the two studies.For the R399Q polymorphism, the n Asians . To furtn Asians . All I2u et al.  in all gPQ = 0.002, I2 = 70.7). Metaregression analysis of data showed that the Ethnicity, Genotyping methods, Bladder cancer confirmation, Source of control, QC when genotyping, and Quality scores were not effect modifiers. Galbraith plots analysis indicated that the study Wu et al. [I2 values decreased obviously and PQ values were greater than 0.10 after excluding the study Wu et al. [PQ = 0.107, I2 = 11.7) and Asians . The signiﬁcance of the ORs for the R280H polymorphism in the overall population and subgroup analyses were not changed by omitting this study.For the R280H polymorphism, significant between-study heterogeneity was also observed in the pooling analyses of total available studies . For the R399Q polymorphism, sensitivity analysis was further performed by omitting the studies by Kelsey et al.  and Andrp values of Egger’s tests were more than 0.05, providing statistical evidence of the funnel plots’ symmetry. The results above suggested that publication bias was not evident in this meta-analysis.Begg’s funnel plot and Egger’s test were performed to access the publication bias of literatures included in this meta-analysis. The shapes of Funnel plot did not reveal obvious evidence of asymmetry, and all the P=0.015 and recessive model AA vs. GA+GG: OR=0.680, 95%CI= 0.515-0.898, P=0.007, respectively). The R194W and R280H polymorphisms were both associated with increased bladder cancer risk among Asians .Previous studies investigating the associations between XRCC1 Polymorphisms and bladder cancer risk have provided inconsistent results, and most of those studies involved no more than a few hundred bladder cancer cases, which is too few to assess any genetic effects reliably. Meta-analysis has been recognized as an important tool to more precisely define the effect of selected genetic polymorphisms on the risk for disease and to identify potentially important sources of between-study heterogeneity. A meta-analysis of 12 studies conducted in 2008  showed tThe bladder, due to being the urine collecting area, is prone to contact with carcinogens. It is well established that the carcinogenesis of bladder cancer is a result of the interaction between environmental factors and genetic background. Besides the role of genetic variants, smoking behavior shows a major effect on the bladder cancer susceptibility . It has P=0.006) but not among Caucasians and Africans, and it was the same with the R280H polymorphism . These inconsistent data among the different ethnicities may indicate different effects of the XRCC1 R194W and R280H polymorphisms on bladder cancer risk in different ethnic genetic backgrounds. Nevertheless, owing to the limited number of relevant studies among Asians and Africans included in this meta-analysis, the observed ethnic difference in this meta-analysis is also likely to be caused by chance because studies with small sample sizes may have insufficient statistical power to detect a slight effect or may have generated a fluctuated risk estimate. Currently there are limited studies on XRCC1 R194W and R280H polymorphisms and bladder cancer risk among Asian populations and African populations. Therefore, large and carefully designed case–control studies need to be performed to provide the best evidence for the possible associations between the XRCC1 R194W and R280H polymorphisms and bladder cancer risk among Asian populations and African populations.When stratified by ethnicity, the R194W polymorphism was associated with increased bladder cancer risk among Asians , which suggested obvious inconsistency of effects across those included studies. To find the major sources of heterogeneity, we first performed several subgroup meta-analyses by ethnicity, smoking status, and by studies in HWE. Subgroup analyses showed that the heterogeneity was still significant in Asians when stratified by ethnicity, while it was removed in the other subgroup analyses, indicating that heterogeneity might result from the inconsistency of effects across those studies included from Asian populations. For the R399Q polymorphism, Galbraith plots spotted 2 studies [Heterogeneity is a potential problem when interpreting the results of all meta-analyses, and finding the sources of heterogeneity is one of the most important goals of meta-analysis . In the  studies ,50 as thSome possible limitations in this meta-analysis should be acknowledged. Firstly, the eligibility criteria for inclusion of cases were different from each other. For instance, the cases in some studies were selected from transitional cell carcinoma ,48, whilDespite these limitations, this meta-analysis suggests that XRCC1 R194W and R280H polymorphisms were both associated with increased bladder cancer risk among Asians. However, the XRCC1 R399Q polymorphism may play a protective role against bladder cancer among smokers. Further studies with larger sample sizes and rigorous design are still needed, especially for investigating the effects of the gene–gene and gene–environment interaction.Figure S1Flow diagram of included studies for this meta-analysis.(TIF)Click here for additional data file.Table S1Checklist of items to include when reporting a systematic review or meta-analysis.(DOC)Click here for additional data file.


Hemocentro de Pernambuco in northeastern Brazil. A case-control comparison showed a significant risk of thrombosis in the presence of Factor V Leiden (OR = 10.1), which was approximately doubled when the AB alleles of the ABO blood group were present as well (OR = 22.3). These results confirm that the increased risk of deep vein thrombosis in the combined presence of AB alleles and Factor V Leiden is also applicable to the Brazilian population suggesting that ABO blood group typing should be routinely added to FVL in studies involving thrombosis.Most cases of a predisposition to venous thrombosis are caused by resistance to activated protein C, associated in 95% of cases with the Factor V Leiden allele (FVL or R506Q). Several recent studies report a further increased risk of thrombosis by an association between the AB alleles of the ABO blood group and Factor V Leiden. The present study investigated this association with deep vein thrombosis (DVT) in individuals treated at the  Deep vein thrombosis (DVT) is one of the main clinical manifestations of venous thromboembolism (VTE). DVT is a multi-factorial disorder caused by genetic and/or acquired abnormalities of the hemostatic mechanism, resulting in hypercoagulation . Hereditet al., 2006; The AB alleles of the ABO blood group, high FVIII levels and von Willebrand factor (vWF) have been associated to a risk of venous thrombosis  with a mean age of 34 years (range 6-67 years) and no familial relationships to one another. All patients had a history of DVT and were treated at the outpatient clinic of the Fundação HEMOPE  between 2001 and 2006. An additional 51 individuals from the same state and with no history of DVT were selected for the control group, which was paired for gender and age group and had no family relationships to one another or to the patients. All samples were collected following the informed consent of the participants.vacutainer tube containing EDTA as the anticoagulant. Genomic DNA was extracted and purified from leukocytes using the GFX genomic DNA purification kit (Amershan Pharmacia Biotech), following the manufacturer's instructions. Genotyping of the ABO system and detection of the R506Q allele in the patients and controls were performed through real-time polymerase chain reaction/allelic discrimination assay using the ABI PRISM 7000 Sequence Detection System (SDS). For the amplification reactions, the Taqman Universal PCR Master Mix  set of reagents was used together with a set of primers and specific probes for the differentiation between the O and A or B genotypes and differentiation between wild alleles and R506Q, designed and synthesized by the Assays-by-Design service (Part Number 4331349) from the sequences of interest sent to Applied Biosystems. In the text and Tables, the genotype designation O refers to absence of any A or B alleles at the ABO locus and AB refers to any of the following: AA, AO, AB, BB, or BO.Peripheral venous blood samples were collected in a sterile Following amplification, the fragments were discriminated by fluorescent data analysis through the software program (version 1.1) on the ABI PRISM 7000 SDS equipment. Statistical analysis was performed by univariate analysis, using the Bioestat 4.0 program  individuals were heterozygotes and carried only a single mutant allele, which is a reasonable assumption given the allele frequency of between 0.02-0.05 seen in many populations. In the patient group, 29.3% had the R506Q allele, whereas only 3.9% in the control group. This led to a highly significant risk of DVT  which was higher than that described in the study by The present study confirms that the association of a combined increased risk of AB alleles and FVL to deep vein thrombosis is also applicable to the population of North Eastern Brazil. We propose that ABO genotyping should be carried out routinely in combination with FVL to evaluate risk for DVT. It would also be of great interest to study whether ABO alleles also have an additive affect in other situations, such as spontaneous abortion or reduced menopausal age, where FVL has also been claimed to play a role.


We sought to determine if a common polymorphism can influence vulnerability to LDL cholesterol, and thereby influence the clinical benefit derived from therapies that reduce LDL cholesterol.We conducted a meta-analysis of the association between a common Trp719Arg polymorphism in the kinesin-like protein 6 (KIF6) gene and the risk of cardiovascular disease (CVD), and a meta-regression analysis to measure the effect modification of this polymorphism on the association between LDL cholesterol and the risk of CVD. We used this measure of genetic effect modification to predict the expected difference in clinical benefit among KIF6 719Arg allele carriers and non-carriers in response to therapies that reduce LDL cholesterol. We then conducted a meta-analysis of statin trials to compare the expected difference in clinical benefit with the observed difference during treatment with a statin.In a meta-analysis involving 144,931 participants, the KIF6 719Arg allele was not associated with the relative risk (RR) of CVD . Meta-regression analysis involving 88,535 participants, however, showed that the 719Arg allele appears to influence the effect of LDL cholesterol on the risk of CVD. KIF6 carriers experienced a 13% greater reduction in the risk of CVD per mmol/L decrease in LDL cholesterol than non-carriers. We interpreted this difference as the expected difference in clinical benefit among KIF6 carriers and non-carriers in response to therapies that lower LDL cholesterol. The difference in clinical benefit predicted by the increased vulnerability to LDL cholesterol among KIF6 carriers  agreed very closely with the observed difference among 50,060 KIF6 carriers and non-carriers enrolled in 8 randomized trials of statin therapy .The KIF6 719Arg allele increases vulnerability to LDL cholesterol and thereby influences the expected clinical benefit of therapies that reduce LDL cholesterol. A common single nucleotide polymorphism (rs20455) results in an argine to tryptophan substitution at position 719 (Trp719Arg) in the gene encoding kinesin-like protein 6 (KIF6). Some One possible explanation is that the KIF6 719Arg allele may increase the risk of cardiovascular disease (CVD), and that treatment with a statin may ameliorate this increased risk through a pleiotropic effect A biologically plausible hypothesis that can potentially reconcile these apparently conflicting findings is that the KIF6 719Arg allele may increase vulnerability to LDL cholesterol. If carriers of the 719Arg allele are more vulnerable to the deleterious effects of LDL cholesterol, then they should experience a greater increase in the risk of CVD per unit increase in LDL, and a correspondingly greater reduction in the risk of CVD per unit decrease in LDL, as compared to non-carriers. Therefore, if KIF6 carriers are more biologically vulnerable to LDL cholesterol, they should derive a greater clinical benefit per unit reduction in LDL cholesterol than non-carriers in response to therapies that lower serum LDL cholesterol levels.The primary aim of our study was to test the hypothesis that a common polymorphism can influence biological vulnerability to LDL cholesterol, and thereby influence the expected clinical benefit of therapies that reduce serum LDL cholesterol levels. To test this hypothesis, we first conducted a systematic review and meta-analysis of the association between the KIF6 719Arg allele and the risk of CVD. We then conducted a meta-regression analysis to measure the effect of the KIF6 719Arg allele on the association between LDL cholesterol on the risk of CVD. We used this measure of effect modification to estimate the expected difference in clinical benefit among KIF6 carriers and non-carriers in response to therapies that lower serum LDL cholesterol level. We then conducted a systematic review and meta-analysis of the effect of the KIF6 719Arg allele on the clinical efficacy of statin therapy. Finally, we compared the expected difference in clinical benefit predicted by the meta-regression analysis with the observed difference in clinical benefit among KIF6 carriers and non-carriers in the meta-analysis of statin trials.We searched Pubmed, Embase, Index of Science, HUGEnet, and Google Scholar, using the search terms: KIF6, rs20455, 719Arg, and Trp719Arg without language restriction; we also checked the abstracts and presentations from major cardiovascular medicine meetings held from 2004 to present First, we conducted an updated systematic review and meta-analysis of the association between KIF6 719Arg carrier status and the risk of CVD. For this analysis, we included case-control studies, epidemiologic cohort studies, and the treatment allocation arms of randomized trials of statin therapy that have reported data separately among KIF6 719Arg allele carriers and non-carriers, but excluded family-based studies. We included both the placebo allocation and statin allocation arms of the placebo controlled trials, as well as both the less intensive and more intensive treatment allocation arms of the trials that compared different treatment intensities of statin therapy. Each treatment allocation arm was considered as a separate prospective cohort study for the purposes of this analysis. For study samples that were included in more than one report, we used data from only the most recent report. In each study, Hardy-Weinberg equilibrium was assessed, as appropriate, using a chi-square test. For each prospective cohort study , we extracted the total number of KIF6 719Arg allele carriers and non-carriers, as well as the number of KIF6 carriers and non-carriers who experienced an incident CVD event during study follow-up. From each case-control study, we extracted the total number of prevalent cases and controls for both KIF6 719Arg allele carriers and non-carriers. We used these data to create 2×2 tables to calculate the unadjusted relative risk (RR), and 95% confidence interval (CI), for each prospective cohort study, and the unadjusted odds ratio (OR), and 95% CI, for each case-control study (as an approximation of the RR) 2) by the effect modification was calculated as the difference in tau2 between the regression model with and without a regression term, expressed as a percentage.Next, we performed a random effects meta-regression analysis to measure the effect modification of study baseline LDL cholesterol level on the association between KIF6 carrier status (and separately KIF6 genotype) and the risk of CVD Finally, we conducted an updated systematic review and meta-analysis of statin trials that have reported results stratified by KIF6 carrier status (or KIF6 genotype). From the report of each randomized trial, we extracted data on the number of persons assigned to either treatment allocation arm and the number of incident CVD events that occurred during study follow-up in each arm, stratified by KIF6 carrier status. We used these data to create 2×2 tables to calculate an unadjusted RR (and 95% CI) for the effect of statin therapy as compared to placebo (or more intensive statin therapy as compared to less intensive statin therapy) on the risk of incident CVD events, separately among KIF6 carriers and non-carriers in each study. All analyses were by the intent-to-treat principle. We then standardized the estimate of the effect of statin therapy per mmol/L reduction in LDL cholesterol across trials by multiplying the natural logarithm of the RR for each trial (and its standard error) by 1÷ Y, where Y is difference in average LDL cholesterol during follow-up between the two treatment allocation arms . We then combined the adjusted RR for each trial using an inverse variance weighted random effects model We standardized the effect of statin therapy per mmol/L reduction in LDL cholesterol in order to compare the observed difference in clinical benefit in the meta-analysis with the expected difference in clinical benefit estimated from the meta-regression analysis using the same scale. Standardizing the effect of statin therapy also allowed us to include both the trials that compared statin with placebo and the trials that compared more intensive and less intensive statin therapy. In the meta-analysis, therefore, the primary measure of effect is not the clinical benefit of statin therapy per se, but rather the clinical benefit per mmol/L reduction in LDL cholesterol during treatment with a statin.2 metric Heterogeneity was measured using Cochran's Q, and the IA total of 37 case-control studies, prospective cohort studies, or randomized trial treatment allocation arms (each considered as a separate cohort), including 144,931 participants and 27,465 CVD events, were included in our meta-analysis of the association between the KIF6 719Arg allele and the risk of CVD  [1]–[6],2 = 58.7%).Among the 37 study samples included in our meta-analysis, 19 prospective cohort studies  involving a total of 88,535 participants and 9,692 incident CVD events, provided information on the average baseline LDL cholesterol level of the population under study and therefore were included in our meta-regression analysis Relying on the symmetrical nature of the effect modification between any two epidemiologic exposures A total of 8 randomized trials, involving 50,060 participants and 7,307 incident cardiovascular events, were included in our meta-analysis of the effect of statin therapy, stratified by KIF6 carrier status  [1]–[6],The magnitude of the difference in clinical benefit per mmol/L reduction in LDL cholesterol observed among KIF6 719Arg carriers and non-carriers in response to treatment with a statin  was nearly identical with the expected difference in clinical benefit per mmol/L reduction in LDL cholesterol predicted by the increased vulnerability to LDL cholesterol among KIF6 719Arg carriers from the meta-regression analysis .Our study demonstrates that the common KIF6 719Arg allele appears to increase vulnerability to LDL cholesterol, and thereby influences the expected clinical benefit from therapies that lower serum LDL cholesterol levels. Persons who inherit one or more copies of the 719Arg allele appear to be more biologically vulnerable to the deleterious effects of LDL cholesterol than non-carriers. As a result, KIF6 719Arg carriers appear to derive a greater reduction in the risk of CVD per mmol/L reduction in LDL cholesterol than non-carriers. The results of our study resolve several apparently conflicting lines of evidence to provide a biologically plausible explanation for how KIF6 carriers can derive a greater clinical benefit from treatment with a statin than non-carriers, even though this polymorphism does not have any impact on the LDL cholesterol lowering effect of statins, and is not independently associated with the risk of CVD.More generally, our study demonstrates that a common polymorphism can influence vulnerability to LDL cholesterol, and thereby influence the expected clinical benefit from therapies designed to lower serum levels of LDL cholesterol. The concept of genetically-mediated differential vulnerability to LDL cholesterol is illustrated in Our study shows that, on average, KIF6 719Arg allele carrier status is not associated with the risk of CVD. Our study also shows, however, that this association varies significantly according to the average baseline LDL cholesterol level of the population under study . FurtherOur findings do not challenge the results of a large-scale meta-analysis of statin randomized trials that found that the clinical benefit of statin therapy is determined largely by the magnitude of LDL cholesterol reduction achieved during treatment Importantly, our study shows that the KIF6 719Arg allele increases vulnerability to LDL cholesterol even though it is not, on average, associated with an increased risk of CVD. This means that all 2.5 million directly genotyped and imputed polymorphism measured in previously conducted genome-wide association studies of CVD, very few of which have been shown to be reliably associated with the risk of CVD Our study has several limitations. Most importantly, we did not have any data on the association between LDL cholesterol and the risk of CVD, stratified by KIF6 carrier status. Therefore, we could not estimate the effect modification of KIF6 on the association between LDL cholesterol and the risk of CVD directly. Instead, we estimated this effect from the meta-regression estimate of the effect modification of LDL cholesterol on the association between the KIF6 719Arg allele and the risk of CVD. We believe this approach is valid because these two estimates of effect modification are equivalent as shown in In conclusion, we found that the common KIF6 719Arg allele appears to increase vulnerability to LDL cholesterol, and thereby influences the expected clinical benefit from therapies that lower serum LDL cholesterol levels. More generally, our study demonstrates that a common polymorphism can influence vulnerability to a common modifiable risk factor for CVD even if it is not independently associated with the risk of CVD. Our study provides a roadmap for further research that could potentially lead to the discovery of polymorphisms that cause large differences in vulnerability to common modifiable risk factors for CVD and thus lead to correspondingly large differences in the clinical benefit derived from therapies used to treat these risk factors. Incorporating such polymorphism into the care of individual patients may help to guide the selection of optimal medical therapies for each individual person based on their genetic background and therefore introduce a practical clinical strategy to personalize the prevention of CVD.Table S1A list of studies included in the meta-analysis of the KIF6 719Arg allele and the risk of cardiovascular disease. The included studies are Atherosclerotic Disease, Vascular Function, and Genetic Epidemiology study (ADVANCE); Acute Myocardial Infarction Gene Study, Dortmund Health Study (AMI Gene Study); CATHGENE Research Project (CATHGENE); deCODE CAD Study (deCODE); National FINRISK studies (FINRISK); German Myocardial Infarction Family Study I (GerMIFS I); German Myocardial Infarction Family Study II (GerMIFS II); Heart Attack in Puget Sound study (HARPS); International Heart Study (INTERHEART); Malmo Diet and Cancer Study (MDS); Washington Hospital Center catheterization study (MEDSTAR); Massachusetts General Hospital study of premature CAD (MGH PCAD); Mid-America Heart Institute (MAHI); Penn-CATH study; Registre Gironi de Cor (REGIGOR); Verona Heart Study (VHS); Wellcome Trust Case Control Consortium CAD Study (WTCCC); Ottawa Heart Study; Cholesterol and Recurrent Events (CARE); West of Scotland Coronary Prevention Study (WOSCOPS); Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI22); Prospective Study of Pravastatin in the Elderly at Risk (PROSPER); Heart Protection Study (HPS); Justification for the Use of Statins in Primary Prevention trial: An Intervention Trial Evaluating Rosuvastatin (JUPITER); Treat to New Targets (TNT); Incremental Decrease in Events through Aggressive Lipid Lowering (IDEAL); Atherosclerosis Risk in Communities study (ARIC); Cardiovascular Health Study (CHS); Women's Health Study (WHS).(PDF)Click here for additional data file.Table S2A description of the baseline characteristics of the randomized trials included in the meta-analysis of the clinical benefit of statin therapy stratified by KIF6 carrier status. The Difference in average LDL (mmol/L) is the difference between either treatment allocation arm. Study acronyms are defined in (PDF)Click here for additional data file.Text S1Equivalent measures of effect modification.(PDF)Click here for additional data file.