Gallbladder cancer predisposition: a multigenic approach to DNA-repair, apoptotic and inflammatory pathway genes

Gallbladder cancer (GBC) is a multifactorial disease with complex interplay between multiple genetic variants. We performed Classification and Regression Tree Analysis (CART) and Grade of Membership (GoM) analysis to identify combinations of alleles among the DNA repair, inflammatory and apoptotic pathway genetic variants in modifying the risk for GBC. We analyzed 16 polymorphisms in 8 genes involved in DNA repair, apoptotic and inflammatory pathways to find out combinations of genetic variants contributing to GBC risk. The genes included in the study were XRCC1, OGG1, ERCC2, MSH2, CASP8, TLR2, TLR4 and PTGS2. Single locus analysis by logistic regression showed association of MSH2 IVS1+9G>C (rs2303426), ERCC2 Asp312Asn (rs1799793), OGG1 Ser326Cys (rs1052133), OGG1 IVS4-15C>G (rs2072668), CASP8 -652 6N ins/del (rs3834129), PTGS2 -1195G>A (rs689466), PTGS2 -765G>C (rs20417), TLR4 Ex4+936C>T (rs4986791) and TLR2 -196 to -174del polymorphisms with GBC risk. The CART analysis revealed OGG1 Ser326Cys, and OGG1 IVS4-15C>G polymorphisms as the best polymorphic signature for discriminating between cases and controls. In the GoM analysis, the data was categorized into six sets representing risk for GBC with respect to the investigated polymorphisms. Sets I, II and III described low intrinsic risk (controls) characterized by multiple protective alleles while sets IV, V and VI represented high intrinsic risk groups (GBC cases) characterized by the presence of multiple risk alleles. The CART and GoM analyses also showed the importance of PTGS2 -1195G>A polymorphism in susceptibility to GBC risk. In conclusion, the present multigenic approach can be used to define individual risk profiles for gallbladder cancer in North Indian population.     

TLR9 -1486T/C and 2848C/T SNPs Are Associated with Human Cytomegalovirus Infection in Infants

Toll-like receptor 9 (TLR9) recognizes non-methylated viral CpG-containing DNA and serves as a pattern recognition receptor that signals the presence of human cytomegalovirus (HCMV). Here, we present the genotype distribution of single-nucleotide polymorphisms (SNPs) of the TLR9 gene in infants and the relationship between TLR9 polymorphisms and HCMV infection. Four polymorphisms (-1237T/C, rs5743836; -1486T/C, rs187084; 1174G/A, rs352139; and 2848C/T, rs352140) in the TLR9 gene were genotyped in 72 infants with symptomatic HCMV infection and 70 healthy individuals. SNP genotyping was performed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Digested fragments were separated and identified by capillary electrophoresis. The HCMV DNA copy number was measured by a quantitative real-time PCR assay. We found an increased frequency of heterozygous genotypes TLR9 -1486T/C and 2848C/T in infants with HCMV infection compared with uninfected cases. Heterozygous variants of these two SNPs increased the risk of HCMV disease in children (P = 0.044 and P = 0.029, respectively). In infants with a mutation present in at least one allele of -1486T/C and 2848C/T SNPs, a trend towards increased risk of cytomegaly was confirmed after Bonferroni’s correction for multiple testing (Pc = 0.063). The rs352139 GG genotype showed a significantly reduced relative risk for HCMV infection (Pc = 0.006). In contrast, the -1237T/C SNP was not related to viral infection. We found no evidence for linkage disequilibrium with the four examined TLR9 SNPs. The findings suggest that the TLR9 -1486T/C and 2848C/T polymorphisms could be a genetic risk factor for the development of HCMV disease.     

Association of genetic polymorphisms in vitamin D receptor gene and susceptibility to sporadic prostate cancer

Genetic and environmental factors are involved in prostate cancer (PCa) etiology. Single nucleotide polymorphisms (SNPs) may contribute to the PCa pathogenesis. The goal of this study is to determine the role of vitamin D receptor (VDR) gene polymorphisms and haplotypes in the development and progression of sporadic PCa. One hundred and thirty-three PCa patients and 157 age-matched healthy controls were genotyped for the Apa I (rs7975232), Bsm I (rs1544410) and Taq I (rs731236) polymorphisms in VDR gene by using polymerase chain reaction-restriction fragment length polymorphism. An association was observed between the Apa I polymorphism and PCa predisposition (P = 0.03). When compared with AA genotype, there was a highly notable difference in the frequencies of the Aa (P = 0.02), aa (P = 0.026) and Apa I 'a' allele carriers (Aa + aa) (P = 0.009) genotypes. Furthermore, we found a statistical difference in the allele frequencies of the Apa I polymorphism between the sporadic PCa patients and control subjects (P = 0.013). The genotype distribution for the Bsm I and Taq I polymorphisms were similar between cases and controls (P > 0.05). No clinically significant relationship was found between the three-locus haplotypes and development of sporadic PCa. The genotype frequencies for the three polymorphisms of the VDR gene within subgroups of PCa (defined by tumor stage, Gleason score, PSA levels) were also analyzed, but no statistically noteworthy difference was observed (P > 0.05). As far as we know, this is the first study which investigates the relationship between VDR genotypes and sporadic PCa in the Turkish population. Our findings suggest that the VDR ApaI (rs7975232) polymorphism may play a role in the development of sporadic PCa.     

Association analysis between MDR1 gene polymorphisms and risk of hepatocellular carcinoma in Chinese population

Objective: XRCC4 play a key role in nonhomologous end-joining repair pathway. Alterations in DNA repair gene have been shown to reduce DNA repair capacity thereby inflicting carcinogenesis.

Methods: In a hospital-based case-control study, 192 prostate cancer (PCa) and 224 healthy controls. They were genotyped for XRCC4 G-1394T (rs6869366), intron 3 (rs28360071) intron 7 (rs28360317) and intron 7 (rs1805377), polymorphisms using polymerase chain reaction–restriction fragment length polymorphism.

Result: Carriers of GG genotype of rs6869366 were at reduced risk. Del/Del of rs28360071 and 28360317 demonstrated increased risk. The haplotype analysis was observed to be associated with a significant increase in PCa risk. Combined genotype of rs6869366, rs28360071 and rs1805377 have shown significant risk with high Gleason grade.

Conclusion: Our results suggested that the variant genotype of XRCC4 rs28360071 and rs28360317 and haplotype analysis may be associated with PCa risk.     

Association of <Emphasis Type="Italic">Toll like receptor 2</Emphasis> and <Emphasis Type="Italic">9</Emphasis> gene variants with pulmonary tuberculosis: exploration in a northern Indian population

Tuberculosis (TB) is a disease of global importance. There is an increasing recognition of the role of Toll like receptors, important pattern recognition receptors of host immune system, in determining the susceptibility or resistance to TB in various populations. In an attempt to examine the importance of Toll like receptors in immune response to Mycobacterium tuberculosis infection, we explored two variants each of TLR2 and TLR9 in a population residing in Uttar Pradesh, India. Genotyping was performed to detect -196 to -174 del polymorphism and G2258A SNP (Arg753Gln, rs5743708) in TLR2 gene and -T1237C (rs5743836) and G2848A (rs352140) SNP in TLR9 gene in patients with pulmonary TB and healthy controls. The A allele of G2848A SNP in TLR9 gene was found with a marginally higher frequency among TB patients as compared to healthy controls, suggesting that A allele at position 2848 of TLR9 gene may be associated with susceptibility to TB in North Indian population [p?=?0.05, Mantel–Haenszel OR?=?1.34, 95% CI (1.0–1.82)].     

Evaluation of Toll-like receptors 3 (c.1377C/T) and 9 (G2848A) gene polymorphisms in cervical cancer susceptibility

Cervical cancer is emerging as a leading cause of morbidity and mortality in women worldwide. Toll-like Receptor (TLR) gene polymorphisms may contribute to subsequent inter-individual variability in cancer susceptibility. The present study aimed to identify the role of TLR 3 (c.1377C/T) [rs3775290] and TLR 9 (G2848A) [rs352140] gene polymorphisms in the risk of developing cervical cancer in North India. Peripheral blood samples were collected from 200 histopathologically confirmed cervical cancer patients from North India and 200 unrelated, cancer-free, age-matched healthy female controls of similar ethnicity. Genomic DNA was extracted using the salting-out method, and genotyped for TLR 3 and TLR 9 using polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). Our data demonstrated a lack of association between TLR 3 (c.1377C/T) and TLR 9 (G2848A) gene polymorphisms and the risk of developing cervical cancer. TLR 3 CT + TT was marginally associated (P = 0.061; age-adjusted OR = 1.46; 95% CI = 0.98–2.16) with cervical cancer susceptibility. The AA genotype of TLR 9 showed borderline significance (P = 0.053) conferring a marginal increased risk (OR = 2.63, 95%CI = 0.99–7.01) for advanced cancer stages (III + IV). Further, TLR 3 and 9 polymorphisms did not have a significant role in modulation of risk due to tobacco usage in cervical cancer patients. Our study suggests only marginal role of TLR 3 and 9 gene polymorphisms in cervical cancer susceptibility in North India; however, future studies in ethnically diverse populations may provide a more comprehensive involvement of innate immunity in cervical cancer etiology in women worldwide.     

Association between VHL single nucleotide polymorphism (rs779805) and the susceptibility to prostate cancer in Chinese

The Von Hippel-Lindau (VHL) tumor suppressor gene is a crucial regulator of the hypoxia response pathway and plays an important role in tumorigenesis, particularly in tumor growth and vascularization. We hypothesize that polymorphisms in the functional region of VHL may influence susceptibility to prostate cancer (PCa). We genotyped a potentially functional polymorphism (rs779805) in 5' UTR region of VHL in a case-control study of 665 PCa patients and 715 cancer-free controls in a Chinese population using the Taqman assay. The genetic associations between the incidence and progression of PCa were assessed by logistic regression. We observed that the rs779805 A>G polymorphism was significantly associated with risk for PCa. Compared with the AA genotype, the AG and AG/GG genotypes were associated with decreased risk of PCa (adjusted odds ratio [OR]=0.79, 95% confidence interval [CI]=0.62-0.99, and adjusted OR=0.76, 95% CI=0.61-0.95, respectively). Further, this decreased risk was more pronounced in the subgroups of nonsmokers (OR=0.73, 95% CI=0.54-0.98), nondrinkers (OR=0.70, 95% CI=0.54-0.91) and patients without family history of cancer (OR=0.72, 95% CI=0.57-0.92). In addition, the decreased risk associated with rs779805 variant genotypes (AG/GG) was more pronounced among the prostate specific antigen (PSA)>20 ng/mL subgroup (OR=0.68, 95% CI=0.49-0.95). Our findings suggest that the rs779805 A>G polymorphism in VHL may confer susceptibility to PCa in the Chinese population.     

Involvement of toll-like receptor 9 polymorphism in cervical cancer development

The role played by the polymorphism located in Toll-like Receptor 9 (TLR9) as a risk factor of cervical cancer remains elusive. Therefore, we studied the association of the TLR9 -1486 T/C (rs187084) and C2848T (rs352140) polymorphisms with cervical cancer. The TLR9 -1486 T/C and C2848T polymorphism was genotyped in 426 patients and 460 unrelated healthy females from the Polish population. Logistic regression analysis adjusting for age, pregnancy, oral contraceptive use, tobacco smoking, and menopausal status showed that both the TLR9 -1486 T/C and C2848T polymorphisms could be a genetic risk factor for cervical cancer. For the TLR9 -1486 T/C polymorphism, the adjusted OR for patients with the C/T genotype versus T/T genotype was 1.371 (95 % CI 1.021-1.842, p = 0.0361), the adjusted OR for the C/C genotype vs the T/T genotype was 1.300 (95 % CI 1.016-1.507, p = 0.0096), and the adjusted OR for the C/T or C/C genotype vs the T/T genotype was 1.448 (95 % CI 1.099-1.908, p = 0.0083). For the C2848T polymorphism, the adjusted OR for patients with the C/T genotype vs C/C genotype was 1.443 (95 % CI 1.019-2.043, p = 0.0380), the adjusted OR for the T/T genotype vs the C/C genotype was 1.237 (95 % CI 1.016-1.507, p = 0.0328), and the adjusted OR for the T/C or T/T genotype vs the C/C genotype was 1.345 (95 % CI 0.976-1.855, p = 0.0700). Our studies suggest that the TLR9 -1486 T/C and C2848T polymorphisms may be a genetic risk factor for cervical cancer.     

Association of caspases with an increased prostate cancer risk in north Indian population

Dysregulation of apoptosis plays a crucial role in carcinogenesis. Thus, genetic alterations within caspase genes would be expected to provoke a deficient apoptotic signaling thereby facilitating the development of prostate cancer (PCa). In the present study we investigated whether three different polymorphisms in the caspase-5 and -3 genes are differentially expressed in PCa. In a hospital-based case control study in northern India, we genotyped 192 PCa patients and 225 unrelated healthy controls for caspase-5 (G>C) (T>C) and caspase-3 (G>A) polymorphisms using amplification refractory mutation system and polymerase chain restriction fragment length polymorphism methods. Data were statistically analyzed and variant genotype GG of caspase-3 demonstrated increased risk for PCa (odds ratio [OR]=2.72, p=0.005). Similarly variant allele carrier (AG+GG) (OR=1.53, p=0.034) and G allele (OR=1.54, p=0.005) were also statistically associated with PCa risk. High risk for PCa was also observed with respect to caspase-5 (CC) diplotypes (OR=21.67, p=0.012, Pc=0.048). We observed significantly enhanced risk for PCa due to interaction between caspase-3 and -5 gene polymorphisms. In association of genotypes with clinical characteristics, heterozygous TC genotype of caspase-5 (T>C) conferred risk with high Gleason grade tumor (OR=2.35, p=0.042). In case-only analysis, interaction of environmental risk factors and genotypes did not further modulate the risk for PCa. Our observations suggested positive association of caspase-3 and diplotype analysis of caspase-5 to be associated with PCa risk. Interaction of caspase-3 and -5 genotypes also modulated the PCa risk.     

Long non-coding RNA POLR2E gene polymorphisms increased the risk of prostate cancer in a sample of the Iranian population

The current study aimed to examine the impact of POLR2E rs1046040 and rs3787016 polymorphisms on prostate cancer (PCa) risk in a sample of southeast Iranian population. The present case-control study was performed on 178 patients with PCa and 180 benign prostatic hyperplasia (BPH). Genotyping of the variants was done by mismatch PCR-RFLP. The findings showed that the rs3787016 C?>?T variant significantly increased the risk of PCa in codominant (OR?=?1.84, 95% CI?=?1.12-3.03, P?=?0.018, CT vs CC), dominant (OR?=?1.88, 95% CI?=?1.63-3.05, P?=?0.011, CT?+?TT vas CC) and allele (OR?=?1.77, 95% CI?=?1.52-2.72, P?=?0.010, T vs C) inheritance model. Regarding rs1046040 C?>?T polymorphism, the findings revealed that the CT genotype significantly increased the risk of PCa compared to the CC genotype (OR?=?1.60, 95% CI?=?1.03-2.49, P?=?0.043). Furthermore, rs3787016 CT/rs1046040?CC as well as rs3787016 CT/rs1046040 CT increased the risk of PCa compared to the CC/CC genotype (p?=?0.029 and p?=?0.014, respectively). Haplotype analysis proposed that rs3787016 T/rs1046040 C significantly increased the risk of PCa compared to C/C (p?=?0.037). No significant association was observed between POLR2E variants and clinicopathological characteristics of PCa patients. In conclusion, the findings propose that POLR2E variants may be a risk factor for susceptibility to PCa in a sample of Iranian population.     

Genetic variation in nucleotide excision repair pathway genes influence prostate and bladder cancer susceptibility in North Indian population

BACKGROUND:

Inherited polymorphisms of XPD and XPC genes may contribute to subtle variations in NER DNA repair capacity and genetic susceptibility to development of urological cancer such as prostate and bladder cancer.

MATERIALS AND METHODS:

We genotyped four Single Nucleotide Polymorphs (SNPs) of the DNA repair gene XPD and XPC in 195 prostate cancer (PCa) and 212 bladder cancer (BC) patients and 250 healthy controls from the same area. XPD Exon 10 (G>A) by amplification refractory mutation system and Exon 23 (A>C), XPC Intron 9 (Ins/Del) and Exon 15 (A>C) were genotyped by PCR-RFLP.

RESULTS:

Variant genotype of XPC demonstrated association with PCa as well as in BC (P, 0.013; P, 0.003). Combined genotype (GA+AA) revealed association with PCa and in BC (P, 0.012, P, 0.002). Variant allele also demonstrated risk in both the cancer. Diplotype of XPD and XPC was associated with a significant increase in PCa and BC risk. Variant (+/+) genotype of XPC intron 9 shown increased risk with PCa and in BC (P, 0.012; P, 0.032). CC genotype of XPC exon 15 revealed increase risk (P, 0.047) with PCa not in BC. In clinopathological grade variant allele of XPC intron 9 and 15 demonstrated risk with high grade of tumor and bone metastasis of PCa. In BC variant allele of XPD exon 10 and 15 also shown association with tumor grade. XPC intron 9 influences the risk of BC in former tobacco users in BC.

CONCLUSIONS:

Our result support that SNPs in XPD and XPC gene may reduce NER repair capacity and play a major role for PCa and BC in North India.     

Polymorphisms in vitamin D receptor,toll-like receptor 2 and Toll-Like receptor 4 genes links with Dengue susceptibility

Host genetic factors are known to determine disease susceptibility in dengue virus infection. Therefore, in this study association of gene polymorphisms of Vitamin D Receptor [rs731236 (Taq) and rs7975232 (Apa1)], Toll-like receptor 2 [rs5743708 (Arg735Gln) and rs5743704 (Pro631His)] and Toll-like receptor 4 [rs4986790A/G(Asp299Gly13843) and rs4986791 C/T(Thr399Ile)] were studied in cases with dengue as compared to controls. Total 98 cases of confirmed dengue virus infection and 98 age, sex and geographically matched healthy controls were enrolled and their genetic polymorphisms for the above mentioned regions were studied by Sanger sequencing. Mutant genotypes CC of VDR rs731236 (Taq1) [(OR 3.808, p value =0.02, CI 1.160-12.498)], GG of VDR rs7975232 (Apa1) [(OR 3.485, p value =0.02, CI 1.162-10.45)] and heterozygous genotypes of TLR4 rs4986790 A/G Asp299Gly [OR 2.40, p value= 0.02, CI 1.12-5.14], TLR4 rs4986791 C/T Thr399Ile [OR 2.09, p value=0.02, CI 1.12-5.14] were found to be significantly more in cases with dengue virus infection as compared to the controls. Also, at these positions mutant alleles were observed in significantly higher number of cases than controls. The values for C allele at VDR rs731236 (Taq1) were OR 1.86, p value 0.009, CI 1.162-3.001; for allele G at rs7975232( Apa1) were OR 2.71, p value 0.006, CI 1.196-2.98 for allele G at TLR4s rs4986790 A/G Asp299Gly were OR 2.35, p value 0.009, CI 1.23-4.50 and for allele T at rs4986791 C/T Thr399Ile were OR 2.36, p value=0.006, CI 1.28-4.38. VDR and TLR4 but not TLR2 gene polymorphisms were found to be associated with dengue susceptibility in Indian population.     

A genetic variant in microRNA-196a2 is associated with increased cancer risk: a meta-analysis

MicroRNAs (miRNAs) are small non-coding RNA molecules that function as negative regulators of gene expression. Common genetic variants (single nucleotide polymorphisms, SNPs) in miRNA genes may alter their expression or maturation resulting in varied functional consequences. Until now, several studies had evaluated the association between the polymorphisms in the hsa-miR-196a2 rs11614913 and cancer risk in diverse populations and in multiple types of cancer, with contradictory outcomes. Therefore, here we performed a meta-analysis to address the association between this polymorphism and cancer risk. A total of nine studies involving 6,540 cases and 7,562 controls were retrieved based on PubMed. Our analysis demonstrated that hsa-miR-196a2 rs11614913 CC genotype significantly increased the cancer risk in homozygote comparison model compared to TT genotype (OR = 1.18; 95% CI, 1.01–1.68). Moreover, significant association of this polymorphism with breast cancer was found based on homozygote comparison model (OR = 1.30; 95% CI, 1.01–1.26) and dominant model (OR = 1.11; 95% CI, 1.01–1.23). In addition, hsa-miR-196a2 rs11614913 CC genotype was significantly associated with cancer risk in Chinese and Indian (OR = 1.21; 95% CI, 1.05–1.40), but not in Caucasians (OR = 1.03; 95% CI, 0.89–1.19). Taken together, our results indicate that the polymorphism of hsa-miR-196a2 rs11614913 is associated with cancer susceptibility, especially with breast cancer and in Chinese and Indian populations.     

Association between ENAM polymorphisms and dental caries in children

AimDental enamel, the most rigid biological tissue of the tooth known to mankind, is the most integral and fundamental part of the tooth. Enamel matrixes compile 5% of Enamelin peptides and at the time of tooth development, they are considered to effect the formation and elongation of enamel crystallites. ENAM plays critical role in enamel formation. Any changes in ENAM may affect the thickness of enamel and may lead to dental caries. The present study is aimed to evaluate the association of ENAM gene polymorphisms and susceptibility of dental caries development risk.Material and methodsThe present study was carried out on 168 South Indian children, children’s with dental caries were included in study. Written consent was taken from their parents/guardians. Additionally 193 healthy individuals were enrolled as controls. Sampling was done after dental examination of the individuals. Three ENAM gene single nucleotide polymorphisms (SNPs) were rs7671281, rs3796704 and rs12640848 was genotyped to check their role in susceptibility of dental caries development risk.ResultsOut of three SNPs rs7671281 showed statistically significant risk association with dental caries susceptibility in this ethnic population at heterozygous allele CT (OR: 1.939, p = .01865) and with minor allele T (OR: 1.451, p = .001292). SNP rs3796704 showed significant protective association with dental caries in Indian population at heterozygous allele GA (OR: 0.409, p = .0192) and with minor allele A (OR: 0.645, p = .00875). SNP rs12640848 showed significant protective association with dental caries in Indian population at heterozygous allele AG (OR: 3.041, p = .00642) and with minor allele G (OR: 1.478, p = .02184). Preliminary insilico analysis also showed that rs7671281 (Ile648Thr) amino acid change will cause the structural and functional changes in ENAM protein.ConclusionsIn the present study significant association was observed between ENAM gene SNP rs7671281 and dental caries susceptibility in South Indian children. These results suggested that ENAM gene variants may contribute to dental caries in children.     

Prostate-specific antigen and 17-hydroxylase polymorphic genotypes in patients with prostate cancer and benign prostatic hyperplasia

We investigated the association of prostate cancer (PCa) and benign prostatic hyperplasia (BPH) with genetic polymorphisms in prostate-specific antigen (PSA) (-158 G/A) and 17-hydroxylase (CYP17) (-34 T/C) genes in a Turkish population. In this study, we investigated the distribution of these polymorphisms in 148 PCa patients, 136 BPH patients, and 102 healthy individuals as controls. The polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism assay. Genotype and allele frequencies were calculated, and their associations with PCa or BPH risk are assayed. The frequency of PSA gene GA and GG genotypes was significantly higher in PCa patients than in controls (p = 0.017 and p = 0.019, respectively). GG genotype was also associated with BPH (p = 0.033). In a case analysis, according to Gleason score, the association of PSA gene GG genotype with Gleason score >7 was near to statistical significance (odds ratio, 2.94; 95% confidence interval, 0.95-9.28). There was also an association between CYP17 polymorphism and BPH (p = 0.004). No association was observed between PCa and CYP17 gene polymorphism. These data demonstrate that PSA gene promoter variation may play a significant role in the development of PCa and BPH, and that CYP17 gene polymorphism may be associated with BPH in the Turkish population studied.     

The Role of TLR2, TLR4 and CD14 Genetic Polymorphisms in Gastric Carcinogenesis: A Case-Control Study and Meta-Analysis

Background

In addition to Helicobacter pylori infection, host genetic factors contribute to gastric cancer (GC). Recognition of H. pylori is known to involve Toll-like receptors (TLR), which subsequently leads to activation of NF-κB. Thus, the overall aim of this study was to estimate for the first time the pooled effect size of polymorphisms in TLR2, TLR4 and CD14 on GC development through a meta-analysis.

Methods

A case-control study comprising 284 ethnic Chinese individuals (70 non-cardia GC cases and 214 functional dyspepsia controls) was conducted for the genotyping of TLR2 -196 to -174del, CD14 -260 C/T and TLR4 rs11536889 using PCR, RT-PCR and mass spectrometry. Case-control studies of TLR2, TLR4 and CD14 polymorphisms and GC were searched up to June 2012. Pooled odds ratios and 95% confidence intervals were obtained by means of the random effects model.

Results

In our ethnic Chinese case-control study, the TLR4 rs11536889 C allele increased the risk of GC (OR: 1.89, 95%CI: 1.23–2.92) while the CD14 -260 T allele was protective (OR: 0.62, 95%CI: 0.42–0.91). TLR2 -196 to -174 increased the risk of GC only in H. pylori-infected individuals (OR: 3.10, 95%CI: 1.27–7.60). In the meta-analysis, TLR4 Asp299Gly showed borderline results in the general analysis (pooled OR: 1.58, 95%CI: 0.98–2.60), nevertheless, stratified analysis by ethnicity showed that the mutant allele was a definitive risk factor for GC in Western populations (pooled OR: 1.87, 95%CI: 1.31–2.65). There was a potential association between the TLR2 -196 to -174 deletion allele and GC in Japanese (pooled OR: 1.18, 95%CI: 0.96–1.45). TLR4 Thr399Ile did not provide significant results.

Conclusions

TLR4 rs11536889 and CD14 -260 C/T are associated with non-cardia GC in Chinese. Based on our meta-analysis, the TLR signalling pathway is involved in gastric carcinogenesis, TLR4 Asp299Gly and TLR2 -196 to -174del showing associations with GC in an ethnic-specific manner.     

C174T polymorphism in the CNTF receptor gene is associated with fat-free mass in men and women.

We performed gene screening of the ciliary neurotrophic factor receptor (CNTFR) gene and genotyped three newly identified polymorphisms: C-1703T in the 5' promoter region, T1069A in intron 5, and C174T in exon 9. We studied the association of these CNTFR variants with muscle strength, mass, and body composition in 465 men and women (20-90 yr) from the Baltimore Longitudinal Study of Aging. Only the C174T variant was significantly associated with muscle-related phenotypes. In the entire cohort, when corrected for age, sex, race, physical activity, and height, homozygotes for the common C allele at C174T (CC) exhibited lower total body mass and body mass index than carriers of the rare T allele, which appeared to be due to significant differences in total nonosseous fat-free mass (FFM) (48.0 +/- 0.4 vs. 50.0 +/- 0.7 kg; P = 0.011) and lower limb FFM (16.5 +/- 0.1 vs. 17.2 +/- 0.2 kg; P = 0.002). The CC group also exhibited significantly lower quadriceps concentric and eccentric isokinetic strength values at both 30 and 180 degrees /s than the T allele carriers (all P < 0.04), but these differences were no longer significant after adjustment for lower limb FFM. There were no significant sex-by-genotype interactions. The results indicate that the C174T polymorphism in exon 9 of CNTFR is significantly associated with FFM in men and women, with concomitant differences in muscular strength.     

REV3L single nucleotide variants lead to increased susceptibility towards non-small cell lung cancer in the population of Jammu and Kashmir

BackgroundNon-small cell lung cancer (NSCLC) is the most common lung cancer, accounting for 80–85% of all lung cancer cases. Various genetic studies have associated REV3L (Protein reversion less 3-like) gene mutations, which encodes the catalytic subunit of error prone translesion synthesis polymerase zeta with cancer, including lung cancer; however, no such data is available from any North Indian population. In this study we attempted to screen the North Indian population of Jammu and Kashmir (J&K) for the potential role of REV3L gene polymorphisms in NSCLC.MethodsA total of four REV3L single nucleotide variants were selected for genotyping based on the available literature. The genotyping was carried out by using the TaqMan allele discrimination assay in 500 subjects (200 NSCLC patients and 300 age and sex matched healthy controls). The association of variants with NSCLC was evaluated by logistic regression.ResultsOut of the four REV3L variants genotyped; rs1002481, rs462779, and rs465646 were found significantly associated with NSCLC risk under the recessive model, with an Odds Ratio (OR) of 3.52(2.14–5.8 at 95% CI, p-value = 0.00000062), 3.7 (1.8–7.6 at 95% CI, p-value = 0.00031), and 2.2 (1.47–3.37 at 95% CI, p-value = 0.0003), respectively.DiscussionOur data supports a strong association between variants rs1002481, rs462779, rs465646 and NSCLC, indicating a potential role of these REV3L variants in increasing the risk for the development of NSCLC in the studied population. Although a first report from any Indian population, these variants have been previously reported to be associated with lung and colorectal cancers in different world populations. Our data along with the existing data supports the notation that these variants can be used as potential genetic predisposition markers.Availability of data and materialsData generated and analysed during study is not available publicly but can be made available from the corresponding author upon reasonable request.