Differential effects of paraoxonase 1 (PON1) polymorphisms on cancer risk: evidence from 25 published studies

Paraoxonase is an HDL-associated enzyme that plays a preventive role against oxidative stress, which is thought to contribute to cancer development. PON1 activity varies widely among individuals, which is in part related to two common nonsynonymous polymorphisms in the PON1 gene (Q192R and L55M). The polymorphisms in PON1 have been implicated in cancer risk. However, results from the studies to date have been conflicting. To clarify the association, a meta-analysis was performed for 7,073 cases and 9,520 controls from 25 published case–control studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. Significant associations between PON1-L55M but not Q192R polymorphism and total cancer were observed from all the comparisons. In stratified analyses, PON1-55M allele was a risk factor for breast cancer. Similarly, increased risk was observed for prostate cancer (OR = 1.18, 95% CI: 1.01–1.36, P _{heterogeneity} = 0.260) and Caucasian population (OR = 1.18, 95% CI: 1.02–1.38, P _{heterogeneity} = 0.1) of the LM genotype, compared with the LL genotype. For PON1-Q192R polymorphism, PON1-192R allele was a decreased risk factor for cancer in the Asian group (RR vs QQ: OR = 0.61, 95% CI: 0.38–0.98, P _{heterogeneity} = 0.268; QR vs QQ: OR = 0.71, 95% CI: 0.52–0.96, P _{heterogeneity} = 0.130; RR + QR vs QQ: OR = 0.71, 95% CI: 0.53–0.95, P _{heterogeneity} = 0.135). Although some modest bias could not be eliminated, this meta-analysis suggests that the PON1-55M allele is a risk factor for the development of cancer, in particular for breast cancer. Future studies with larger sample sizes are warranted to further evaluate these associations.     

Paraoxonase 1 192 and 55 polymorphisms in osteosarcoma

Paraoxonase is an HDL-associated enzyme that plays a preventive role against oxidative stres. Previous studies suggested that involved an amino acid substitution at position 192 gives rise to two alloenzymes with a low activity (Q allele) and a high activity (R allele) towards paraoxon. There also exists a second polymorphism of the human PON1 gene affecting amino acid 55, giving rise to a leucine (L-allele) substitution for methionine (M-allele). PON1 gene polymorphisms were studied in 50 patients with osteosarcoma and 50 healthy controls. Paraoxonase genotypes were determined by PCR–RFLP. We found a reduction in the frequency of PON1 192 R allele in patients (P = 0.015). Besides, PON1 192 wild type QQ genotype (P = 0.015) and PON1 55 wild type L allele (P = 0.001) were higher in patients compared to healthy controls. PON1 192 QQ genotype was associated with osteosarcoma in multivariate logistic regression analysis. Our findings have suggested that PON1 192 wild type genotypes may be associated with a risk of developing osteosarcoma.     

Effects of selected genetic polymorphisms in xeroderma pigmentosum complementary group D on gastric cancer

DNA repair capacity (DRC) can be altered based on sequence variations in DNA repair genes, which may result in cancer susceptibility. The current study was to evaluate the association between genetic polymorphisms, including associated haplotypes of xeroderma pigmentosum complementary group D (XPD), and individual susceptibility to gastric cancer. Two-hundred-eight patients with gastric cancer and 339 healthy controls were enrolled in this study. Their genomic DNA was extracted from peripheral blood leukocytes. The genotypes at exon 6, 10 and 23 were identified by polymerase chain reaction (PCR). Unconditional logistic regression model was used to analyze the effects of the polymorphisms, including the corresponding haplotypes, on the susceptibility to develop gastric cancer. The proportion of genotypes GA or AA at exon 10 in cases was showed to be significantly higher than that in controls (P < 0.01, P < 0.01, respectively). The risk of genotype GA or AA carriers to develop gastric cancer was simultaneously much higher (OR = 3.38, 95% CI 2.30–4.95; OR = 6.13, 95% CI 2.45–15.31, respectively). The allele A at exon 10 was also observed to manifest a substantially higher frequency in cases compared to controls (P < 0.01), which might indicate an increased tendency to gastric cancer (OR = 2.40, 95% CI 1.81–3.17). No significant differences were found in the distribution of genotypes at exon 6 or 23 between the two groups (P = 0.23, P = 0.52; P = 0.44, P = 0.56, respectively). By haplotype analysis, haplotype AAA could individually increase incidence of gastric cancer (P < 0.01, OR = 3.39, 95% CI 2.21–5.21). In contrast, haplotypes CGA and AGA were showed a decline in gastric cancer susceptibility (OR = 0.67, 95% CI 0.46–0.97; OR = 0.58, 95% CI 0.41–0.83, respectively). The rest of haplotypes made no statistically significant difference between cases and controls. Taken together, this study demonstrates that the genetic variation at exon 10 and haplotype AAA may be contributing factors in developing gastric cancer.     

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.     

Association between TNF-α polymorphisms and cervical cancer risk: a meta-analysis

Tumor necrosis factor alpha (TNF-α) is a vital cytokine involved in inflammation, immunity, and cellular organization. The TNFA-308G/A (rs1800629) and -238G/A (rs361525) polymorphisms are two widely investigated variants for their associations with risk of cervical cancer, but the results are conflicting. Here, we performed a meta-analysis to pool the data and evaluate the between-studies heterogeneity. All the case–control studies published from January 1989 to October 2010 on the association between the two polymorphisms of TNFA and cervical cancer risk were identified by searching the electronic literature Medline. The cervical cancer risk associated with the two polymorphisms of TNFA gene was estimated for each study by OR together with its 95% CI, respectively, by using the Review Manager 4.2 software. It was showed that the variant homozygote -308AA was associated with a significantly increased risk of cervical cancer (AA vs. GG: OR = 1.41, 95% CI = 1.03–1.92, P = 0.033; AA vs. GA/GG: OR = 1.39, 95% CI = 1.02–1.90, P = 0.036), and the effect was more evident among Asians (AA vs. GA/GG: OR = 3.67, 95% CI = 1.25–10.81, P = 0.018). We also found that the variant genotypes -238GA/AA was associated with a significantly decreased risk of cervical cancer (GA/AA vs. GG: OR = 0.55, 95% CI = 0.41–0.74, P < 0.001). The results suggested that TNFA-308G/A and -238G/A may contribute to cervical cancer susceptibility.     

Quantitative assessment of the effect of MTHFR polymorphisms on the risk of lung carcinoma

Published studies on the relationships between 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and lung cancer risk have been conflicting. To derive a more precise estimation of the relationship, a meta-analysis was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between MTHFR C677T and A1298C polymorphisms and lung cancer risk. A total of 15 studies including 10,753 cases and 11,275 controls described C677T genotypes, among which 11 articles totalling 6,161 cases and 7,684 controls described A1298C genotypes, were also involved in this meta-analysis. Overall, no significantly elevated lung cancer risk was found in any genetic models when all studies were pooled. For C677T polymorphism: (TT vs. CC: OR = 1.17, 95% CI = 0.97–1.42; TC vs. CC: OR = 1.06, 95% CI = 0.94–1.20; dominant model: OR = 1.09, 95% CI = 0.96–1.24; and recessive model: OR = 1.08, 95% CI = 0.95–1.24); for A1298C polymorphism: (CC vs. AA: OR = 1.04, 95% CI = 0.91–1.19; AC vs. AA: OR = 0.98, 95% CI = 0.91–1.06; dominant model: OR = 0.99, 95% CI = 0.92–1.06; and recessive model: OR = 1.05, 95% CI = 0.92–1.20). In the subgroup analyses, the results showed that 677T varients could decrease lung cancer risk in female (OR = 0.63, 95% CI = 0.41–0.95, P-value = 0.03, 677CC as reference). No evidence of any associations of MTHFR A1298C polymorphism with lung cancer was found in overall or subgroup analyses. Our meta-analysis supports that the common polymorphisms of C677T and A1298C in MTHFR gene are not susceptibility gene for lung cancer from currently available evidence.     

Thymidylate synthase and methionine synthase polymorphisms are not associated with susceptibility to childhood acute lymphoblastic leukemia in Kurdish population from Western Iran

In order to determine the influence of polymorphism in thymidylate synthase (TS 28-bp repeat) and methionine synthase (MS A2756G) genes on the susceptibility to acute lymphoblastic leukemia (ALL), 73 children with ALL and 128 age and sex matched unrelated healthy individuals from the Kermanshah Province of Iran were screened. The genotyping of TS 28-bp repeat and MS A2756G polymorphisms were performed by polymerase chain reaction (PCR) and PCR–RFLP, respectively. The frequency of TS 2R allele in patients and controls were 41.5 and 38%, respectively (Odds ratios (OR) = 1.13, 95%CI 0.73–1.74, P = 0.56). The allelic frequency of G allele of MS was higher (25%) in patients compared with healthy subjects (23%) (OR = 1.09, 95%CI 0.67–1.75, P = 0.71). Considering MS AA and TS 3R3R genotypes as reference indicated that individuals with MS GG + TS 2R2R genotypes have 1.3-fold increase in the risk of ALL (OR = 1.3, 95%CI 0.6–2.7, P = 0.5). Our results showed that neither TS 28-bp repeat nor MS A2756G polymorphisms are risk factors for susceptibility to ALL in Western Iran.     

European versus Asian differences for the associations between paraoxonase‐1 genetic polymorphisms and susceptibility to type 2 diabetes mellitus

Many studies have examined the associations between paraoxonase‐1 (PON1) genetic polymorphisms (Q192R, rs662 and L55M, rs854560) and the susceptibility to type 2 diabetes mellitus (T2DM) across different ethnic populations. However, the evidence for the associations remains inconclusive. In this study, we performed a meta‐analysis to clarify the association of the two PON1 variants with T2DM risk. We carried out a systematic search of PubMed, Embase, CNKI and Wanfang databases for studies published before June 2017. The pooled odds ratios (ORs) for the association and their corresponding 95% confidence intervals (CIs) were calculated by a random‐ or fixed‐effect model. A total of 50 eligible studies, including 34 and 16 studies were identified for the PON1 Q192R (rs662) and L55M (rs854560) polymorphism, respectively. As for the PON1 Q192R polymorphism, the 192R allele was a susceptible factor of T2DM in the South or East Asian population (OR > 1, P < 0.05) but represented a protective factor of T2DM in European population (OR = 0.66, 95% CI = 0.45–0.98) under a heterozygous genetic model. With regard to the PON1 L55M polymorphism, significant protective effects of the 55M allele on T2DM under the heterozygous (OR = 0.77, 95% CI = 0.61–0.97) and dominant (OR = 0.80, 95% CI = 0.65–0.99) genetic models were found in the European population, while no significant associations in the Asian populations under all genetic models (P > 0.05). In summary, by a comprehensive meta‐analysis, our results firmly indicated that distinct effects of PON1 genetic polymorphisms existed in the risk of T2DM across different ethnic backgrounds.     

Implication of genetic variants near TMEM18, BCDIN3D/FAIM2, and MC4R with coronary artery disease and obesity in Chinese: a angiography-based study

Coronary artery disease (CAD) is multifactorial disease which occurs as a result of the interaction of genetic and environmental factors. Obesity is an independent risk factor for cardiovascular disease. Recent genome-wide association studies have identified several genes associated with obesity in Europeans. We wondered whether these genetic variants were associated with CAD. Three single nucleotide polymorphisms (SNPs) rs7561317 near TMEM18, rs7138803 near BCDIN3D/FAIM2 and rs12970134 near MC4R were examined in 930 Han Chinese subjects based on coronary angiography, using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) analysis. There were no significant differences in genotypes and allele distributions of three SNPs between CAD and CAD-free groups. The AA genotype of SNP rs12970134 near MC4R was associated to obesity both in CAD group and CAD-free group in Han Chinese population (P < 0.001, OR = 2.96, 95% CI 2.01–3.73; and P = 0.003, OR = 2.59, 95% CI 1.86–3.19, respectively). Our observations suggest that the polymorphism rs12970134 near MC4R may be associated to the risk of obesity in Han Chinese population.     

Association of +45(T/G) and +276(G/T) polymorphisms in the adiponectin gene with coronary artery disease in a population of Iranian patients with type 2 diabetes

The relation of Two single nucleotide polymorphisms (SNPs) at the adiponectin locus (+45T/G and +276G/T) with coronary artery disease (CAD) is controversial. The aim of the present study was to evaluate the genetic influence of the adiponectin gene polymorphisms in the development of CAD among patients with Type 2 diabetes (T2D). The adiponectin genotypes were detected by polymerase chain reaction and restriction analysis (PCR-RFLP) in our patients. Two adiponectin gene (ADIPOQ) SNPs (i.e. SNPs +45T>G and +276G>T) were genotyped in 114 Type 2 diabetic subjects with CAD, and 127 Type 2 diabetic patients without CAD. Demographic and anthropometric data along with plasma biochemistry including lipids, glycemic indices, and adiponectin were collected. There was a significant difference in the distribution of genotypes of +45T/G and +276G/T between CAD and non-CAD individuals (P < 0.05). Based on our results SNP+276G>T is associated with decreased risk of CAD after adjustment for potential confounding factors [adjusted OR = 0.39 (95%CI: 0.22–0.68); P = 0.001]. Similar findings were not observed for the +45T>G SNP. Two haplotypes 45T-276T and 45G-276T were associated with a decreased risk of CAD [adjusted OR = 0.47 (95% CI: 0.32–0.94); P = 0.03 and adjusted OR = 0.33 (95% CI: 0.13–0.83); P = 0.02 respectively]. No significant difference was observed between HOMA-IR, BMI, waist circumference, history of hypertension, HbA1C, and lipid concentrations regarding the two SNPs. In conclusion, these findings suggest that T allele of +276G>T SNP is significantly associated with decreased risk of CAD in T2D Patients. Also Haplotype analysis showed that two haplotypes 45T-276T and 45G-276T were associated with a decreased risk of CAD.     

15-Lipoxygenase gene variants are associated with carotid plaque but not carotid intima-media thickness

The major underlying cause of CHD is atherosclerosis, and oxidised LDL is known to play an important role in its development. We examined the role of three single nucleotide polymorphisms (SNPs) in the 15-lipoxygenase gene (ALOX15), in atherosclerosis. We genotyped three SNPs in the ALOX15 promoter in two Western Australian samples—1,111 community-based individuals and 556 with CHD. SNPs and haplotypes were tested for an association with carotid plaque, intima-media thickness and risk of CHD. The −611GG genotype was associated with increased likelihood of carotid plaque in CHD patients (OR = 4.01, 95%CI = 1.39–11.53, P = 0.005) and the C alleles of the G-220C and G-189C SNPs were associated with decreased likelihood of plaque among cases (OR = 0.66, 95%CI = 0.43–0.99, P = 0.05 and OR = 0.51, 95%CI = 0.34–0.78, P = 0.002 respectively). The GGG haplotype was associated with increased risk of carotid plaque in CHD patients (OR = 5.77, 95%CI = 1.82–18.29, P = 0.0007) and in community-based individuals under 53 years (OR = 4.15, 95%CI = 1.23–14.08, P = 0.02). No association was observed between ALOX15 SNPs or haplotypes and intima-media thickness. This study is novel as it is the first to examine the association between 15-lipoxygenase polymorphisms and atherosclerotic indicators. These findings suggest a possible role of ALOX15 polymorphisms in focal plaque formation.     

Meta-analysis of TYK2 gene polymorphisms association with susceptibility to autoimmune and inflammatory diseases

The aim of our meta-analysis was to quantitatively summarize the association of TYK2 gene polymorphisms with autoimmune and inflammatory diseases. 11 studies that included data from 21497 cases and 22647 controls were identified. OR was used as a measure of the effect of the association in a fixed/random effect model. Meta-analysis was performed for six TYK2 gene polymorphisms (rs34536443, rs2304256, rs280523, rs280519, rs12720270 and rs12720356). Significant association was found in rs34536443 (C versus G: OR = 0.76, 95% CI = 0.69–0.84, P < 0.00001; GC + CC versus GG: OR = 0.78, 95% CI = 0.68–0.90, P = 0.0005; CC versus GG + GC: OR = 0.76, 95% CI = 0.28–2.05, P = 0.58; CC versus GG: OR = 0.74, 95% CI = 0.27–2.02, P = 0.56; GC versus GG: OR = 0.78, 95% CI = 0.68–0.90, P = 0.0006) and rs2304256 (A versus C: OR = 0.78, 95% CI = 0.70–0.87, P < 0.0001; CA + AA versus CC: OR = 0.69, 95% CI = 0.59–0.81, P < 0.0001; AA versus CC + CA: OR = 0.75, 95% CI = 0.66–1.00, P = 0.05; AA versus CC: OR = 0.64, 95% CI = 0.47–0.86, P = 0.003; CA versus CC: OR = 0.70, 95% CI = 0.60–0.83, P < 0.0001) in TYK2 gene, but not for the other polymorphisms (rs280523, rs280519, rs12720270, and rs12720356). This meta-analysis demonstrates that autoimmune and inflammatory diseases is associated with TYK2 gene rs34536443 and rs2304256 polymorphisms, but not rs280523, rs280519, rs12720270 and rs12720356.     

A meta-analysis of three polymorphisms in the endothelial nitric oxide synthase gene (NOS3) and their effect on the risk of diabetic nephropathy

A number of association studies have investigated the role of the nitric oxide synthase 3 (NOS3) gene in the development of diabetic nephropathy (DN). However, results have been inconclusive, largely because the studies have focused on a variety of different polymorphisms and generate inconsistent results. We performed a meta-analysis of 28 association studies focusing on three polymorphisms in the NOS3 gene (G894T (Glu289Asp), 4b/a, and T-786C) and the risk of DN published before July 2009, covering a total of 10,364 subjects. Although significant heterogeneity was initially found in the analysis of G894T, it did not remain when analysis was done by ethnic subgroups. 894T was negatively associated with DN in Caucasian populations of European origin (OR = 0.896, 0.817–0.983, 95% CI), but was positively associated with DN in East Asian (OR = 2.02, 1.20–3.42, 95% CI) and other populations. Association of the 4b/a variant was observed when studies involving microalbuminuria were excluded (OR = 1.19, 1.02–1.39, 95% CI). The T-786C variant showed an overall weak association (OR = 1.16, 1.01–1.34, 95% CI) with little heterogeneity. In summary, our meta-analysis of the effect of NOS3 gene polymorphisms on the risk of DN supports the involvement of the NOS3 gene in the pathogenesis of DN.     

Association between two genetic polymorphisms of the renin-angiotensin-aldosterone system and diabetic nephropathy: a meta-analysis

The widely studied candidate genes of the renin-angiotensin-aldosterone system, angiotensinogen (AGT), and angiotensin II receptor type 1 (AGTR1), are implicated in the development of diabetic nephropathy (DN). A number of studies have evaluated the association between the functional polymorphisms, AGT M235T and AGTR1 A1166C, and DN risk with conflicting results. The present meta-analysis was performed to estimate the overall risk of these polymorphisms associated with DN on 4,377 DN cases and 4,905 controls from 34 published case–control studies by searching electronic databases and reference lists of relevant articles. We examined the association between each polymorphism and the risk of DN by odds ratio (OR) with 95% confidence intervals (95% CI) and calculated the ORs for different genetic model. In addition, stratification analysis by ethnicity and diabetes mellitus (DM) type was conducted. In this meta-analysis, we failed to find any significant main effects in both overall analysis and stratified analysis for the AGT M235T. However, the overall analysis detected a significant association between the AGTR1 A1166C and the risk of DN for the CC compared with the AA and dominant genetic model (CC vs. AA: OR = 2.10, 95% CI: 1.00–4.44; dominant model: OR = 2.11, 95% CI: 1.06–4.23). In subgroup analysis, only patients with T2DM showed significant association for CC vs. AA model and dominant model (CC vs. AA: OR = 3.31, 95% CI: 1.21–9.08; dominant model: OR = 3.50, 95% CI: 1.41–8.69). This study suggests that the AGTR1 A1166C polymorphism may contribute to DN development, particularly in T2DM patients.     

Association of ERCC2/XPD polymorphisms and interaction with tobacco smoking in lung cancer susceptibility: a systemic review and meta-analysis

The association of the two ERCC polymorphisms, Asp312Asn and Lys751Gln, with lung cancer risk remains controversial and inconclusive. To better evaluate the potential role of the two polymorphisms and interaction with tobacco smoking in lung cancer susceptibility presented in diverse populations, we have conducted a meta-analysis based on 26 studies from 24 publications which included analyses of Asp312Asn (7121 cases, 8962 controls) and Lys751Gln (8396 cases, 10510 controls) polymorphisms. Overall, significantly elevated lung cancer risk was associated with ERCC2 312Asn allele(homozygous model: OR = 1.20[1.05–1.36], P = 0.006; recessive model: OR = 1.20[1.06–1.35], P = 0.004) and 751Gln allele(homozygous model: OR = 1.31[1.17–1.46], P < 0.00001; heterozygous model: OR = 1.11[1.04–1.19], P = 0.003; recessive model: OR = 1.23[1.11–1.37], P < 0.0001; dominant model: OR = 1.15[1.08–1.23], P < 0.0001). In ethnic subgroup analyses, significantly increased risk was associated with ERCC2 312Asn allele for both Caucasians and Asians, and 751Gln allele for both Caucasians and Latino-Americans. When stratified by smoking status, significantly elevated risk of both polymorphisms for never-smokers was detected (dominant model, OR = 1.46[1.09–1.95] and 1.57[1.19–2.08], P = 0.01 and 0.002, respectively). In conclusion, this meta-analysis suggests that the two ERCC2 polymorphisms may contribute to lung cancer susceptibility serving as low-penetrance risk factors. Extremely large-scale evidence would be necessary to confirm the effects on ethnically specific populations and gene-environment interactions.     

Association analysis of p16 (CDKN2A) and RB1 polymorphisms with susceptibility to cervical cancer in Indian population

The potent tumor suppressors P16 and RB1 are the key regulators of cell cycle machinery in eukaryotes. Polymorphisms in these genes play an important role in the outcome of various diseases including cancer. In the present study, we evaluated the association of p16 and RB1 polymorphisms with cervical cancer susceptibility in Indian population. We screened 150 histologically confirmed cervical cancer cases along with equal number of healthy controls with normal cervical cytology. PCR-RFLP method was employed for genotyping of SNPs in p16 C540G (rs11515), C580T (rs3088440) in the 3′-UTR of exon 3 and RB1 A153104G (rs4151580) located in the intron 18 and confirmed by direct sequencing. Both patients and controls were screened for HPV infection. In this case–control study 84.67% (127/150) of cases were found to be positive for HPV DNA sequence. Women carrying p16 C540G carrier genotypes 540 (CG/GG) may have protective effect for the development of cervical cancer (P = 0.0001, OR = 0.31, 95% CI = 0.17–0.56). And SNP at C580T of p16 gene was found to be negatively associated with the risk of cervical cancer (P = 0.0004, OR = 0.04, 95% CI = 0.002–0.63). p16 (540C/580T) has emerged as a major risk haplotype (P = 0.033, OR = 1.47, 95% CI = 1.05–2.07) whereas p16 (540G/580T) as a chief protective haplotype (P = 0.014, OR = 0.39, 95% CI = 0.18–0.83) for the development of cervical cancer among Indian women. Contrary to this, SNP at A153104G of RB1 gene showed statistically significant association (P = 0.035, OR = 1.69, 95% CI = 1.06–2.68) with increased susceptibility for the development of cervical cancer. Our results suggest that single nucleotide polymorphisms in p16, RB1 genes may affect the susceptibility to cervical cancer collectively.     

Genetic diversity of the apolipoprotein E gene and diabetic nephropathy: a meta-analysis

In the past decade, a number of case–control studies have been carried out to investigate the relationship between the ApoE polymorphism and diabetic nephropathy. However, the results have been inconclusive. To investigate this inconsistency, we performed a meta-analysis of all available studies dealing with the relationship between the ApoE polymorphism and DN. The 23 studies in the meta- analysis included 6,012 diabetic patients with (n = 2,979) and without (n = 3,033) DN. The ApoE ε2 allele was significantly associated with DN (OR = 1.64, 95% CI: 1.26–2.13; P(Z) = 0.00027), whereas the ε4 allele was non-significantly associated with DN (OR = 0.93, 95% CI: 0.78–1.11; P(Z) = 0.418). However, significant heterogeneity was detected. In further subgroup analyses, genotyping methods, outcome of cases and duration of diabetes in controls were found to explain some of the heterogeneity. Genotypic analysis also found a strong association between the ε2 carriers and DN (OR = 1.61, 95% CI: 1.22–2.13; P(Z) = 0.001) and indicated that ε4 tended to have a marginally significant protective effect for DN (OR = 0.82, 95% CI: 0.65–1.03; P(Z) = 0.085). The results of our meta-analysis support a genetic association between the ApoE polymorphism and DN. ε2 increases the risk of DN in diabetes patients, while ε4 trends to be protective. These findings may have implications for therapeutic intervention in diabetic nephropathy.     

CDH1 promoter polymorphism and stomach cancer susceptibility

The relationship of stomach cancer susceptibility and the presence of E-cadherin (CDH1) promoter −160 C/A polymorphism had been reported with conflicting results. To further explore the association of this polymorphism with stomach cancer susceptibility, we performed an extensive search of relevant studies and carried out a meta-analysis to obtain a more precise estimate. A total of 16 studies including 2,611 cases and 3,788 controls were involved in this meta-analysis. When all studies involved, the meta-analysis results suggest no statistically significant association between CDH1 −160 C/A polymorphism and stomach cancer risk (CA vs. CC: OR = 1.01, 95% CI: 0.85–1.19; AA vs. CC: OR = 1.05, 95% CI: 0.75–1.46; dominant model: OR = 1.02, 95% CI: 0.86–1.20; recessive model: OR = 1.04, 95% CI: 0.76–1.41). When subgroup analyses were performed by ethnicity, the A-allele carriers conferred a decreased stomach cancer risk in Asians (AA vs. CC: OR = 0.67, 95% CI: 0.47–0.96; dominant model: OR = 0.85, 95% CI: 0.72–0.99), but no statistically significant association was found in Caucasians. In conclusion, this meta-analysis suggests that CDH1 −160 A-allele may play a protective role of stomach cancer development in Asians but not in Caucasians.     

Role of p53 and p73 genes polymorphisms in susceptibility to esophageal cancer: a case control study in a northern Indian population

Genetic variants in p53 and in its homologue p73 may modulate Esophageal Cancer (EC) risk because they are supposed to influence cell cycle progression, apoptosis and DNA repair. Therefore, we aimed to evaluate the association of p53 intron3 16 bp duplication and p73 G4C14-to-A4T14 polymorphisms with susceptibility to EC in a northern Indian population in 255 EC patients and 255 age and sex matched healthy controls. We found that p53 intron3 16 bp duplication polymorphism was not associated with EC and its clinical characteristics. However, p73 G4C14-to-A4T14 polymorphism was associated with significant higher risk of EC (OR = 1.74, 95% CI = 1.16–2.60, P = 0.007) in an allele dose-dependent manner (P_trend = 0.0047). Stratification of subjects on the basis of clinical characteristics showed that p73 AT genotype carriers were at significant increased risk of developing esophageal squamous cell carcinoma (OR = 1.78, 95% CI = 1.18–2.67, P = 0.006) at middle third tumor location (OR = 1.87, 95% CI = 1.18–2.97, P = 0.007) with lymph node metastasis (OR = 1.77, 95% CI = 1.04–3.02, P = 0.035). No interaction with environmental risk factors was observed with any of the studied polymorphisms. In summary, p73 G4C14-to-A4T14 polymorphism but not the p53 intron3 16 bp duplication polymorphism is associated with EC and its clinical characteristics in northern Indian population.     

A common variant in the adiponectin gene and polycystic ovary syndrome risk

In this study, we explored whether polymorphisms in insulin receptor (INSR), adiponectin (ADIPOQ), parathyroid hormone (PTH), and vitamin D receptor (VDR) genes are associated with polycystic ovary syndrome (PCOS). A total of 362 subjects, including 181 women with PCOS and 181 controls were enrolled in this case-control study. Two SNPs (rs2059806 and rs1799817) in the INSR gene, two SNPs (rs2241766 and rs1501299) in the ADIPOQ gene, one SNP (rs6256) in the PTH gene, and one SNP (rs757343) in the VDR gene were analyzed using PCR-RFLP method. We observed no significant difference in genotype and allele frequencies between the women with PCOS and controls for the rs2059806, rs1799817, rs1501299, rs6256, and rs757343 polymorphisms either before or after adjustment for confounding factors including age and BMI. However, the ADIPOQ rs2241766 “TT” genotype compared with “TG and GG” genotypes was associated with a 1.93-fold increased risk for PCOS (P = 0.006, OR = 1.93, 95% CI = 1.20–3.11), and the differences remained significant after adjustment for age and BMI (P = 0.039, OR = 1.72, 95% CI = 1.03–2.86). Furthermore, the ADIPOQ rs2241766 “T” allele was significantly overrepresented in women with PCOS than controls (P = 0.006; OR = 1.80, 95% CI = 1.18–2.70), and the difference remained significant after Bonferroni correction. Our findings suggest that the ADIPOQ rs2241766 “TT” genotype is a marker of increased PCOS susceptibility. This study also indicates for the first time that there are no significant association between INSR rs2059806, PTH rs6256, and VDR rs757343 gene polymorphisms and PCOS risk. However, these data remain to be confirmed in larger studies and in other populations.