Genetic polymorphisms in the CYP1A1 and CYP1B1 genes and susceptibility to bladder cancer: a meta-analysis

The current meta-analysis of case–control studies was conducted to evaluated the relationships of genetic polymorphisms in the CYP1A1 and CYP1B1 genes with the susceptibility to bladder cancer, aiming at determine whether these polymorphisms may contribute to the pathogenesis of bladder cancer. Related articles were determined via searching the following electronic databases without any language restrictions: PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases for relevant articles published before November 1st, 2013. STATA 12.0 software was also selected to deal with statistical data. The relationships were evaluated using the pooled odds ratios (ORs) and their 95 % confidence intervals (CI). Eleven case–control studies with a total of 2,609 bladder cancer patients and 2,634 healthy subjects met the inclusion criteria. The results of our meta-analysis demonstrated that CYP1A1 genetic polymorphisms were associated with increased risks of bladder cancer (allele model: RR = 1.18, 95 % CI 1.07–1.30, P = 0.001; dominant model: RR = 1.15, 95 % CI 1.05–1.27, P = 0.003; respectively), especially among 11599G>C, 2455A>G, 3810T>C, and 113T>C polymorphisms. A subgroup analysis by ethnicity was conducted to investigate its effect on susceptibility to bladder cancer. The subgroup analysis results revealed positive significant correlations between CYP1A1 genetic polymorphisms and bladder cancer risk among Asians (allele model: RR = 1.26, 95 % CI 1.10–1.44, P = 0.001; dominant model: RR = 1.22, 95 % CI 1.08–1.38, P = 0.001), but not among Caucasians (all P < 0.05). Nevertheless, we observed no significant correlations between CYP1B1 genetic polymorphisms and bladder cancer risk (all P > 0.05). Our meta-analysis indicates that CYP1A1 genetic polymorphisms may be involved in the pathogenesis of bladder cancer, especially among 11599G>C, 2455A>G, 3810T>C, and 113T>C polymorphisms. However, CYP1B1 genetic polymorphisms may not be important determinants of bladder cancer susceptibility.     

ESR1 Gene Polymorphisms and Prostate Cancer Risk: A HuGE Review and Meta-Analysis

Background

Many published data on the association between single nucleotide polymorphisms (SNPs) in the ESR1 gene and prostate cancer susceptibility are inconclusive. The aim of this Human Genome Epidemiology (HuGE) review and meta-analysis is to derive a more precise estimation of this relationship.

Methods

A literature search of PubMed, Embase, Web of Science and Chinese Biomedical (CBM) databases was conducted from their inception through July 1st, 2012. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of association.

Results

Twelve case-control studies were included with a total 2,165 prostate cancer cases and 3,361 healthy controls. When all the eligible studies were pooled into the meta-analysis, ESR1 PvuII (C>T) and XbaI (A>G) polymorphisms showed no association with the risk of prostate cancer. However, in the stratified analyses based on ethnicity and country, the results indicated that ESR1 PvuII (C>T) polymorphism was significantly associated with increased risk of prostate cancer among Asian populations, especially among Indian population; while ESR1 XbaI (A>G) polymorphism may significantly increase the risk of prostate cancer among American population. Furthermore, we also performed a pooled analysis for all eligible case-control studies to explore the role of codon 10 (T>C), codon 325 (C>G), codon 594 (G>A) and +261G>C polymorphisms in prostate cancer risk. Nevertheless, no significant associations between these polymorphisms and the risk of prostate cancer were observed.

Conclusion

Results from the current meta-analysis indicate that ESR1 PvuII (C>T) polymorphism may be a risk factor for prostate cancer among Asian populations, especially among Indian population; while ESR1 XbaI (A>G) polymorphism may increase the risk of prostate cancer among American population.     

Association between the CYP1A1 T3801C polymorphism and risk of cancer: Evidence from 268 case–control studies

T3801C is a common polymorphism in CYP1A1, showing differences in its biological functions. Case–control studies have been performed to elucidate the role of T3801C in cancer, although the results are conflicting and heterogeneous. Hence, we performed a meta-analysis to investigate the association between cancer susceptibility and T3801C (55,963 cases and 76,631 controls from 268 studies) polymorphism in different inheritance models. We used odds ratios with 95% confidence intervals to assess the strength of the association. Overall, significantly increased cancer risk was observed in any genetic model (dominant model: odds ratio [OR] = 1.14, 95% confidence interval [CI] = 1.09–1.19; recessive model: OR = 1.23, 95% CI = 1.12–1.34; CC vs. TT: OR = 1.31, 95% CI = 1.19–1.45; TC vs. TT: OR = 1.12, 95% CI = 1.07–1.18; additive model: OR = 1.14, 95% CI = 1.09–1.19) when all eligible studies were pooled into the meta-analysis. In further stratified and sensitivity analyses, the elevated risk remained for subgroups of cervical cancer, head and neck cancer, hepatocellular cancer, leukemia, lung cancer, prostate cancer and breast cancer. In addition, significantly decreased colorectal cancer risk was also observed. In summary, this meta-analysis suggests that the participation of CYP1A1 T3801C is a genetic susceptibility for some cancer types. Moreover, our work also points out the importance of new studies for T3801C association in some cancer types, such as gallbladder cancer, Asians of acute myeloid leukemia, and thyroid cancer, where at least some of the covariates responsible for heterogeneity could be controlled, to obtain a more conclusive understanding about the function of the CYP1A1 T3801C polymorphism in cancer development.     

Association between 3801T>C Polymorphism of CYP1A1 and Idiopathic Male Infertility Risk: A Systematic Review and Meta-Analysis

Background

Epidemiological studies have evaluated the association between 3801T>C polymorphism of CYP1A1 gene and the risk for idiopathic male infertility, but the results are inconclusive. We aimed to derive a more precise estimation of the relationship by conducting a meta-analysis of case-control studies.

Methods

This study conformed to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase and CNKI databases were searched through November 2013 to identify relevant studies. Pooled odds ratios with 95% confidence intervals were used to assess the strength of the association between CYP1A1 3801T>C polymorphism and idiopathic male infertility risk. Q-test was performed to evaluate between-study heterogeneity and publication bias was appraised using funnel plots. Sensitivity analyses were conducted to evaluate the robustness of meta-analysis findings.

Results

Six studies involving 1,060 cases and 1,225 controls were included in this meta-analysis. Overall, significant associations between 3801T>C polymorphism and idiopathic male infertility risk were observed in allelic comparison (OR = 1.36, 95% CI: 1.01–1.83), homozygous model (OR = 2.18, 95% CI: 1.15–4.12), and recessive model (OR = 1.86, 95% CI: 1.09–3.20), with robust findings according to sensitivity analyses. However, subgroup analyses did not further identify the susceptibility to idiopathic male infertility in all comparisons. Funnel plot inspections did not reveal evidence of publication bias.

Conclusions

The current meta-analysis provides evidence of a significant association between CYP1A1 3801T>C polymorphism and idiopathic male infertility risk. Considering the limitation inherited from the eligible studies, further confirmation in large-scale and well-designed studies is needed.     

−765G>C and 8473T>C polymorphisms of COX-2 and cancer risk: a meta-analysis based on 33 case–control studies

Cyclooxygenase-2 (COX-2) is an inducible enzyme converting arachidonic acid to prostaglandins and playing important roles in cancer etiology. The −765G>C and 8473T>C polymorphisms have been implicated in cancer risk. However, the results on the association between the two COX-2 polymorphisms and cancer risk are conflicting. To derive a more precise estimation of the association between them, we performed a meta-analysis of 8,090 cancer cases and 11,010 controls concerning −765G>C polymorphism and 14,283 cancer cases and 15,489 controls concerning 8473T>C polymorphism from 33 case–control studies. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Overall, individuals with the −765GC or GC/CC genotypes were associated with higher cancer risk than those with the −765GG genotype and in the stratified analysis this effect maintained in colorectal carcinoma or esophageal cancer of Asian descents. Overall, no significant cancer risk of 8473T>C polymorphism was found. Stratified by cancer types, the variant 8473CC was associated with a decreased risk in breast cancer, compared with the TT or TC/TT genotypes and in lung cancer subgroup after sensitive analysis, there was a decreased risk in CC versus TT, TC versus TT and the dominant models. Moreover, a decreased risk of lung cancer was observed among smokers in the dominant model. In summary, this meta-analysis suggesting that −765G>C may cause an increased risk of colorectal carcinoma and esophageal cancer in Asian descents while 8473T>C polymorphism may cause a decreased risk of breast and lung cancer.     

CYP1A1 MspI polymorphism is associated with prostate cancer susceptibility: evidence from a meta-analysis

Cytochrome P450 1A1 (CYP1A1), an important phase I xenobiotic metabolizing enzyme, is responsible for metabolizing numerous carcinogens, particularly polycyclic aromatic hydrocarbons. The genetic polymorphism of CYP1A1 at the site of MspI (CYP1A1 MspI) has been implicated in prostate cancer risk, but the results of individual studies remain conflicting and inconclusive. The aim of this meta-analysis was to investigate the association of CYP1A1 MspI polymorphism with prostate cancer risk more precisely. We performed a comprehensive search of the PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases from their inception up to September 20, 2012 for relevant publications. The pooled odds ratios with the corresponding 95 % confidence intervals (95 % CIs) were calculated to assess the association of CYP1A1 MspI polymorphism with prostate cancer risk. In addition, stratified analyses by ethnicity and sensitivity analyses were conducted for further estimation. Sixteen eligible publications with 6,411 subjects were finally included into the meta-analysis after checking the retrieved papers. Overall, meta-analysis of total studies suggested that individuals carrying the TC genotype and a combined C genotype (CC + TC) were more susceptible to prostate cancer (OR_{TC vs. TT} = 1.33, 95 % CI 1.10–1.61, P _OR = 0.004; OR_{CC+TC vs. TT} = 1.27, 95 % CI 1.05–1.55, P _OR = 0.016). Stratified analysis of high quality studies also confirmed the significant association (OR_{TC vs. TT} = 1.32, 95 % CI 1.04–1.67, P _OR = 0.024; OR_{CC+TC vs. TT} = 1.30, 95 % CI 1.02–1.66, P _OR = 0.035). In subgroup analyses by ethnicity, a significant association between the CYP1A1 MspI polymorphism and risk of prostate cancer was found among Asians (OR_{TC vs. TT} = 1.44, 95 % CI 1.20–1.72, P _OR < 0.001; OR_{CC+TC vs. TT} = 1.33, 95 % CI 1.12–1.58, P _OR = 0.001), but not in Caucasians or mixed populations. The meta-analysis suggests an important role of the CYP1A1 MspI polymorphism in the risk of developing prostate cancer, especially in Asians.     

Polymorphism T→C of gene CYP17 promoter and polycystic ovary syndrome risk: a meta-analysis

The T → C polymorphism of CYP17 gene has been inconsistently associated with polycystic ovary syndrome (PCOS) risk. We examined the association by performing a meta-analysis. Two investigators independently searched the Medline, Embase, CNKI, and Chinese Biomedicine Databases. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) for CYP17 polymorphism and PCOS were calculated in a fixed-effects model and a random-effects model when appropriate. The pooled ORs were performed for co-dominant model (CC vs. TT, TC vs. TT), dominant model (CC + TC vs. TT), and recessive model (CC vs. TC + TT). Subgroup analyses were performed by ethnicity, country, Hardy-Weinberg equilibrium (HWE) in controls and study sample size. This meta-analysis included 10 case-control studies, which included 1321 PCOS cases and 1017 controls. Overall, the variant genotypes (CC and TC) were not associated with PCOS risk, compared with the wild-type TT homozygote. Similarly, no associations were found in the dominant and recessive models. Stratified analyses by ethnicity/country also detected no significant association. However, limiting the analysis to the studies within HWE, a significantly increased risk was observed (TC vs. TT, OR = 1.44, 95% CI = 1.10-1.88; dominant model, OR = 1.41, 95% CI = 1.10-1.81). Moreover, when stratifying by study sample size, a significantly elevated risk was found among small sample studies (≤ 200 subjects), but not among large sample studies (> 200 subjects). This meta-analysis suggests that the CYP17 T/C polymorphism may be not associated with PCOS risk, while the observed increase in risk of PCOS may be due to small-study bias.     

Prostate cancer with variants in CYP17 and UGT2B17 genes: a meta-analysis

Both CYP17 and UGT2B17 are suggested to be potential risk factors of prostate cancer (PCa). To date, many studies have evaluated the relationship between CYP17 T-34C and UGT2B17 Del polymorphisms and Prostate cancer with conflicting results. Here, we performed comprehensive meta-analyses of over 25 studies, including results from about 17,000 subjects on the association of CYP17 T-34C and UGT2B17 Del polymorphisms with Prostate cancer. Overall, no significant associations between CYP17 T-34C polymorphism and Prostate cancer risk were found for T versus C (P=0.63), TT versus CC (P=0.52), TT+TC versus CC (P=0.40) or TT versus TC+CC (P=0.98), though there was a marginally significant association with the UGT2B17 Del polymorphism under Del/Del versus Ins/Ins +Ins/Del (P=0.05). In an analysis of various subgroups, there were no substantially significant associations with the CYP17 T-34C polymorphism; while there was a significant association for the UGT2B17 Del/Del genotype in a subgroup of men-based controls (P < 0.0001). The current meta-analysis results suggest that the CYP17 T-34C polymorphism may not be associated with Prostate cancer, while the UGT2B17 Del polymorphism may significantly contribute to prostate cancer susceptibility in men. These findings also support the idea that CYP17 has no significant effects on androgen levels, while UGT2B17 does.     

Meta-Analysis of the Association between COX-2 Polymorphisms and Risk of Colorectal Cancer Based on Case–Control Studies

Objective

Cyclooxygenase-2 (COX-2) is an inducible enzyme converting arachidonic acid to prostaglandins and playing important roles in inflammatory diseases as well as tumor development. Previous studies investigating the association between COX-2 polymorphisms and colorectal cancer (CRC) risk reported conflicting results. We performed a meta-analysis of all available studies to explore this association.

Methods

All studies published up to October 2013 on the association between COX-2 polymorphisms and CRC risk were identified by searching electronic databases PubMed, EMBASE, and Cochrane library. The association between COX-2 polymorphisms and CRC risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs).

Results

Ten studies with 6,774 cases and 9,772 controls were included for −1195A>G polymorphism, 13 studies including 6,807 cases and 10,052 controls were available for −765G>C polymorphism, and 8 studies containing 5,121 cases and 7,487 controls were included for 8473T>C polymorphism. With respect to −765G>C polymorphism, we did not find a significant association with CRC risk when all eligible studies were pooled into the meta-analysis. However, in subgroup analyses by ethnicity and cancer location, with a Bonferroni corrected alpha of 0.05/2, statistical significant increased CRC risk was found in the Asian populations (dominant model CC+CG vs. GG: OR = 1.399, 95%CI: 1.113–1.760, P = 0.004) and rectum cancer patients (CC vs. GG: OR = 2.270, 95%CI: 1.295–3.980, P = 0.004; Recessive model CC vs. CG+GG: OR = 2.269, 95%CI: 1.297–3.970, P = 0.004). In subgroup analysis according to source of control, no significant association was detected. With respect to −1195A>G and 8473T>C polymorphisms, no significant association with CRC risk was demonstrated in the overall and subgroup analyses.

Conclusions

The present meta-analysis suggests that the COX-2 −765G>C polymorphism may be a risk factor for CRC in Asians and rectum cancer patients. Further large and well-designed studies are needed to confirm this association.     

Association between CASP3 polymorphisms and overall cancer risk: A meta-analysis of case-control studies

Several studies inspected the relationship between caspase-3 (CASP3) polymorphisms and the risk of several human cancers, but the findings remain controversial. We conducted a meta-analysis aiming to inspect the association between CASP3 rs1049216 T>C, rs12108497 C>T, rs4647603 G>A, rs4647602 C>A, rs6948 T>G, rs2705897 A>C, and rs113420705 G>A polymorphisms and cancer risk. Eligible studies were recognized by searching the Web of Science, PubMed, Scopus, and Google Scholar databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to quantitatively evaluate the association between each polymorphism of CASP3 and cancer risk. The rs4647603 variant significantly increased the risk of cancer in an overdominant (OR, 1.44; 95% CI, 1.03-2.01; P = 0.03; AG vs AA+GG) inheritance model. Regarding the rs4647602 variant, the findings revealed that this variant was associated with protection against cancer in homozygous codominant (OR, 0.67; 95% CI, 0.56-0.80; P < 0.00001; AA vs CC), dominant (OR, 0.84; 95% CI, 0.73-0.96; P = 0.009; AC+AA vs CC), recessive (OR, 0.70; 95% CI, 0.61-0.79; P < 0.00001; AA vs AC+CC), and allele (OR, 0.81; 95% CI, 0.75-0.88; P = 0.00001; A vs C) models. The findings suggested that the rs2705897 variant significantly decreased the risk of cancer in heterozygous codominant (OR, 0.80; 95% CI, 0.67-0.94; P = 0.009; AC vs AA), dominant (OR, 0.81; 95% CI, 0.69-0.95; P = 0.009; AC+CC vs AA), overdominant (OR, 0.80; 95% CI, 0.68-0.95; P = 0.01; AC vs CC+AA), and allele (OR, 0.85; 95% CI, 0.74-0.97; P = 0.02; C vs A) models. The results did not support an association between CASP3 rs1049216 and rs6948 polymorphisms and cancer risk. In summary, the findings of this meta-analysis support an association between CASP3 polymorphisms and cancer risk. Larger and well-designed studies are desired to evaluate these associations in detail.     

Functional polymorphisms in the interleukin-12 gene contribute to cancer risk: Evidence from a meta-analysis of 18 case–control studies

Background

Emerging evidence from preclinical and clinical studies has shown that interleukin-12 (IL-12) has some effectiveness against endogenously arising carcinogenesis. Several potentially functional polymorphisms of IL-12 gene have been implicated in cancer risk, but individually published studies showed inconclusive results. The aim of this study was to investigate the association between IL-12 polymorphisms and cancer risk.

Methods

The MEDLINE, EMBASE, Web of science and CBM databases were searched for all articles published up to June 10, 2012 that addressed IL-12 polymorphisms and cancer risk. Statistical analyses were performed using RevMan 5.1.6 and STATA 12.0 softwares.

Results

Eighteen studies were included with a total of 6463 cancer cases and 7412 healthy controls. We found that the 3'UTR A > C (rs3212227) polymorphism of IL-12B gene was associated with significantly increased overall risk of cancers using random effects model (C vs A: odds ratio [OR] = 1.14, 95% confidence interval [CI]: 1.02-1.27; AC + CC vs AA: OR = 1.20, 95%CI: 1.01-1.43). However, the 3'UTR G > A (rs568408), IVS2 T > A (rs582054) and 5'UTR T > G (rs2243115) polymorphisms of IL-12A gene did not appear to have an influence on cancer susceptibility. Further subgroup analyses showed that the 3'UTR A > C (rs3212227) polymorphism was associated with increased cancer risks in the subgroups of Asians, cervical and nasopharyngeal cancers.

Conclusions

Results from the current meta-analysis indicates that the 3'UTR A > C (rs3212227) polymorphism of IL-12B gene might be a potential biomarker for cancer risk among Asians, especially for cervical and nasopharyngeal cancers.     

Cytochrome P450 1A1 (CYP1A1) gene polymorphisms and cervical cancer risk: a meta-analysis

This meta-analysis aims to examine whether the genotype status of MspI and Ile462Val polymorphisms in Cytochrome-P450 1A1 (CYP1A1) is associated with cervical cancer risk. Eligible case-control studies were identified through search in MEDLINE (end of search: October 2010). Pooled odds ratios (ORs) were appropriately derived from fixed-effects or random effects models. Concerning MspI polymorphism, six studies were eligible (722 cases and 770 controls); four studies were eligible (350 cases and 519 controls) for Ile462Val. MspI polymorphism was associated with elevated cervical cancer risk (for heterozygous TC vs. TT carriers OR = 1.50, 95% CI: 0.93–2.42, random effects; for homozygous CC vs. TT carriers OR = 2.66, 95% CI: 1.14–6.19, random effects). Similarly, Ile462Val polymorphism was associated with elevated cervical cancer risk (for heterozygous Ile/Val vs. Ile/Ile carriers OR = 2.36, 95% CI: 1.10–5.08, random effects; for homozygous Val/Val vs. Ile/Ile carriers OR = 2.73, 95% CI: 1.21–6.15, fixed effects). The results were replicated upon Caucasian subjects, who represented the majority of existing data. The two examined CYP1A1 genotype polymorphisms seem to confer additional risk for cervical cancer. Accumulation of further data seems mandatory for future race-specific analyses and for the demonstration of CYP1A1-smoking interactions.     

Current evidence on the relationship between CYP1B1 polymorphisms and lung cancer risk: a meta-analysis

The association between single-nucleotide polymorphisms (SNPs) of the CYP1B1 gene and lung cancer risk is still ambiguous. In this meta analysis, we assessed 10 case–control studies included 7,067 cases and 9,374 controls of the association between CYP1B1 SNPs of Leu432Val (rs1056836, 432C>G), Asn453Ser (rs1800440, 453A>G), Ala119Ser (rs1056827, 119G>T), Arg48Gly (rs10012, 48C>G) and the risk of lung cancer. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of association between the polymorphism and lung cancer risk under codominant model, dominant model and additive model respectively. Although there were limitations, this meta analysis indicated that individuals with 432GG genotype had a 39.7% higher risk of having lung cancer than those with the 432CC genotype, and individuals with the 432G allele had a 26.3% increased risk as well. An increased risk of lung cancer of 2.13 fold was observed in individuals with 119TT genotype. For Arg48Gly, individuals with 48GG genotype had a significantly increased risk of lung cancer compared with individuals with 48CC (OR 3.859; 95% CI 2.536–5.87). Elevated risk of lung cancer were observed in dominant model (OR 2.115; 95% CI 1.653–2.705) as well. The risk of lung cancer was elevated as the frequency of G allele increased in additive model (P = 0.000). For individuals with the polymorphism at codon 453, no evidence of such association was observed. Furthermore, a possible association between the CYP1B1 polymorphism at codon 432 and the lung cancer could be detected in individuals of Caucasian origin, while a negative association was suggested in Asians and African-Americans. An increased lung cancer risk was also found in women with polymorphism at codon 453. These results are supportive for the hypothesis that the CYP1B1 432GG, 119TT and 48GG genotypes are low-penetrance risk factors for developing lung cancer, and further studies are needed to validate these associations.     

Genetic association of <Emphasis Type="Italic">Phosphodiesterase 1B</Emphasis> (PDE1B) with carcass traits in Korean cattle

Quantitative trait loci for fat deposition and carcass traits have been identified in the vicinity of the gene encoding phosphodiesterase 1B (PDE1B) on bovine chromosome 5. Therefore, the PDE1B gene can be considered as a positional and functional candidate gene for carcass traits in beef cattle. This study aimed to identify single nucleotide polymorphisms (SNPs) in the PDE1B gene and to evaluate their associations with carcass traits in Korean cattle. Eight SNPs, g.440T>G, g.17122A>G, g.17507A>C, g.17575A>G, g.17607T>C, g.17609C>A, g.17692C>T, and g.17707C>G, were identified in the region ranged from exon 1 to intron 6. Five of them were used for association analysis because of their availability of restriction fragment length polymorphisms. As a result, g.17122A>G in intron 3 was significantly associated with backfat thickness (BFT), and g.17507A>C in exon 5 was associated with longissimus dorsi muscle area (LMA, P < 0.05). Animals with the AG genotype of g.17122 had thicker BFT than those with the AA genotype. Animals with the AA or AC genotype of g.17507A>C had larger LMA than those with the CC genotype. We suggested the PDE1B gene as a candidate gene for carcass traits of beef cattle. Fine mapping would be required for application to marker-assisted selection.     

MTHFR 677C>T and 1298A>C polymorphisms and male infertility risk: a meta-analysis

Epidemiological studies have evaluated the association between MTHFR 677C>T and 1298A>C polymorphisms and risk of male infertility. However, the results from the published studies on the association between these two MTHFR polymorphisms and male infertility risk are conflicting. To derive a more precise estimation of association between the MTHFR polymorphisms and risk of male infertility, we performed a meta-analysis. A comprehensive search was conducted to identify all case–control studies of MTHFR polymorphisms and male infertility risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Overall, we found that both 677C>T and 1298A>C polymorphisms were not significantly associated with male infertility risk. However, in stratified analysis by ethnicity, we found that the 677C>T polymorphism was significantly associated with the risk of male infertility in Asian population (TT vs. CC: OR = 1.57, 95% CI: 1.05–2.37, P = 0.03; TT vs. TC + CC: OR = 1.40, 95% CI: 1.05–1.86, P = 0.02; TT + TC vs. CC: OR = 1.34, 95% CI: 1.01–1.77, P = 0.04). Although some modest bias could not be eliminated, this meta-analysis suggested that the MTHFR 677T allele might be a low-penetrant risk factor for male infertility, especially in Asian population.     

Analysis of the cytochrome P450 1A1 (CYP1A1) gene polymorphism in the ethnic groups of the republic of Bashkortostan

In three ethnic groups from the Republic of Bashkortostan, Russians (N = 451), Tatars (N= 333), and Bashkirs (N = 171), allele, genotype, and haplotype frequency distribution patterns of the CYP1A1 gene single nucleotide polymorphisms, A2455G and T33801C, were investigated. Substantial interethnic differences in the allele frequency distribution patterns of the CYP1A1 polymorphisms A2455G and T3801C (χ ² = 15.61, d.f. = 2, P = 0.0001; and χ ² = 22.10, d.f. = 2, P = 0.0001, respectively) were observed. Pairwise comparison showed that ethnic groups of Tatars and Russians were similar in the A2455G allele frequencies (χ ² = 1.10, d.f. = 1, P = 0.30). However, in case of the T3801C marker, statistically significant differences were revealed (χ ² = 4.56, d.f. = 1, P = 0.032). At the same time, Bashkir ethnic group was found to be statistically significantly different from Russians and Tatars in the CYP1A1 polymorphic allele frequency distribution patterns (χ ² = 15.74, d.f. = 2, P = 0.0001; and χ ² = 7.47, d.f. = 1, P = 0.024, for A2455G, and χ ² = 6.46, d.f. = 1, P = 0.011; and χ ² = 21.36, d.f. = 1, P = 0.0001, for T3801C). Analysis of the CYP1A1 haplotype diversity showed that in terms of the CYP1A1 haplotype frequency distribution patterns, Bashkir ethnic group was statistically significantly different from both Russians (χ ² = 30.07, d.f. = 3, P = 0.0001) and Tatars (χ ² = 11.28, d.f. = 3, P = 0.013). The differences observed were caused by the high frequency of haplotype CYP1A1*2B, which was represented by a combination of rare alleles of the CYP1A1 polymorphisms A2455G and T3801C in Bashkirs (5.81%). On the other hand, the ethnic groups of Russians and Tatars residing in the Republic of Bashkortostan were characterized by similar frequencies of the CYP1A1 haplotypes (χ ² = 6.322, d.f. = 3, P = 0.127). The data obtained could be used in further investigations of the genetic bases of ecology dependant diseases and in the risk groups in the Republic of Bashkortostan.     

No impact of SLCO1B1 521T>C, 388A>G and 411G>A polymorphisms on response to statin therapy in the Greek population

Interindividual variability exists in statin lipid-lowering response, partially attributed to genetic factors. Organic anion-transporting polypeptide 1B1 (OATP1B1) encoded by SLCO1B1 gene (solute carrier organic anion transporter family member 1B1) facilitates hepatic uptake of simvastatin and atorvastatin. SLCO1B1 polymorphisms are strongly associated with statin-induced myopathy whereas few studies have assessed their effect on statin differential response. In the present study, we analyzed the association of SLCO1B1 521T>C, 388A>G and 411G>A polymorphisms with response to atorvastatin and simvastatin in 386 adults (201 atorvastatin-treated and 185 simvastatin-treated) with primary hypercholesterolemia, all of Greek origin. Total cholesterol and low-density lipoprotein cholesterol were measured at baseline and on 6 months of treatment. Genetic polymorphisms were analyzed by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) method. A novel RFLP protocol was developed for the simultaneous identification of 388A>G and 411G>A polymorphisms. SLCO1B1 521T>C, 388A>G and 411G>A polymorphisms were not associated with lipid-lowering response to atorvastatin or simvastatin. No sex-gene or statin dose-gene interaction was observed on the effect of the analyzed SLCO1B1 polymorphisms in statin lipid lowering response in either statin-treated patient cohort. Further studies in different populations are required to draw firm conclusion on the potential association of SLCO1B1 polymorphisms with statin lipid-lowering response.     

CYP1A1 MspI polymorphisms and lung cancer risk: an updated meta-analysis involving 20,209 subjects

Published data describing the association between CYP1A1 MspI gene polymorphism and lung cancer risk are inconclusive. To determine a more conclusive relationship, we performed an updated meta-analysis of all eligible studies and conducted the subgroup analysis by stratification according to the ethnicity source, histological types of lung cancer, gender and smoking status of case and control populations. A total of 51 studies comprising 20,209 subjects were included in the analysis. A significantly elevated lung cancer risk was associated with two variant genotypes (for TT vs CC: OR=1.24, 95% CI=1.11-1.40; for CT and TT combined vs CC: OR=1.19, 95% CI=1.12-1.27) in the overall population. In the stratified analysis, significantly higher risks associated with lung cancer were found in Asians, Caucasians, lung SCC, lung AC and the male population. In contrast, negligible risks were found in the mixed population, lung SCLC and the female population. Additionally, a significant association was found in the smoker population, whereas no association was found in non-smoker populations. This meta-analysis suggests that the MspI polymorphisms of CYP1A1 correlate with increased lung cancer susceptibility, and that there is an interaction between the CYP1A1 polymorphism and smoking. However, the associations vary in different ethnic populations, histological types of lung cancer and the gender of case and control populations.     

Association of eNOS polymorphisms (-786T>C, 4a4b, 894G>T) with colorectal cancer susceptibility in the Korean population

Background

Polymorphisms of endothelial nitric oxide synthases (eNOS) have been shown to be associated with cancer susceptibility. However, the results of such studies are conflicting to date. We investigated whether polymorphisms of the eNOS gene correlated with patients with colorectal cancer (CRC), relative to healthy individuals.

Patients and methods

In the present study, we analyzed three polymorphisms of eNOS (-786T>C, 4a4b, and 894G>T) in 509 healthy controls and 528 patients with CRC. The genotyping of eNOS polymorphisms was performed using polymerase chain reaction or polymerase chain reaction–restriction fragment length polymorphism assays.

Results

We found that the TC+CC genotype of the -786T>C polymorphism was significantly associated with an increased risk of CRC compared with the TT genotype. Similarly, the GT+TT genotype of the 894G>T polymorphism was associated with an increased susceptibility to CRC. However, no evidence was found for any association between the 4a4b polymorphism and CRC risk. In addition, the C/4b/G (-786T>C/4a4b/894G>T) haplotype was significantly associated with increased risk of CRC and C/4b/T (-786T>C/4a4b/894G>T) haplotype was only detected in CRC patients.

Conclusions

Our study suggests that the eNOS -786T>C and 894G>T polymorphisms may be associated with the development of CRC in the Korean population.     

Cyclin D1 G870A polymorphism and breast cancer risk: a meta-analysis comprising 9,911 cases and 11,171 controls

Cyclin D1 represents a key molecule in the regulation of cell cycle. CCND1 G870A (rs603965) polymorphism has drawn considerable attention as the A allele may generate a variant splice product with possible oncogenic actions. A meta-analysis examining the association between CCND1 G870A polymorphism and breast cancer risk was performed. Separate analyses on Caucasian and Chinese populations were also implemented. Eligible articles were identified for the period up to July 2010. Pooled odds ratios (OR) were appropriately derived from fixed-effects or random-effects models. Sensitivity analysis excluding studies whose genotype frequencies in controls significantly deviated from Hardy–Weinberg Equilibrium (HWE) was performed. Nine case–control studies on Caucasians (7,304 cases and 8,149 controls) and four case–control studies on Chinese (2,607 cases and 3,022 controls) were eligible. At the overall analysis the A allele seemed to be associated with elevated breast cancer risk; the effect seemed to be confined to homozygous carriers (pooled OR = 1.091, 95% CI: 1.008–1.179, P = 0.030, fixed effects) as heterozygous carriers did not exhibit significantly elevated breast cancer risk. No statistically significant associations were demonstrated in Caucasians. On the other hand, Chinese AA carriers exhibited marginally elevated breast cancer risk (pooled OR = 1.144, 95% CI: 0.984–1.329, P = 0.080, fixed effects). Nevertheless, the controls in two out of the four Chinese studies deviated from HWE. In conclusion, this meta-analysis suggests that the A allele of the CCND1 G870A polymorphism may confer additional breast cancer risk when it comes to homozygosity and Chinese populations. The need for additional, methodologically sound studies on Chinese populations seems warranted.