Glutathione S-Transferase P1 313 (A > G) Ile105Val Polymorphism Contributes to Cancer Susceptibility in Indian Population: A Meta-analysis of 39 Case-Control Studies.

GSTP1 involved in the metabolism of carcinogens and toxins, reduces damage of DNA and act as a suppressor of carcinogenesis. Many studies have reported that 313 A > G polymorphism is associated with different cancer in Indian population, but the results remain conflicting rather than conclusive. Therefore, we have performed meta-analysis to clarify the more precise association of GSPT1 313 A > G polymorphism with cancer risk in Indian population. We retrieved all relevant published literature from PubMed (Medline) and Google scholar web database and included those study only based on the established inclusion criteria. Pooled ORs and 95% CIs were used to appraise the strength of association. Publication bias and sensitivity analysis was also evaluated. A total of 6581 confirmed cancer cases and 8218 controls were included from eligible thirty nine case-controls studies. Pooled analysis suggested that the variant genotypes significantly increased the risk of cancer in allele (G vs. A: OR 1.266, 95% CI 1.129-1.418, p = 0.001), heterozygous (AG vs. AA: OR 1.191, 95% CI 1.047-1.355, p = 0.008), homozygous (GG vs. AA: OR 1.811, 95% CI 1.428-2.297, p = 0.001), dominant (GG + AG vs. AA: OR 1.276, 95% CI 1.110-1.466, p = 0.001) and recessive (GG vs. AG + AA: OR 1.638, 95% CI 1.340-2.002, p = 0.001) genetic models. The stability of these observations was confirmed by a sensitivity analysis. Begger's funnel plot and Egger's test did not reveal any publication bias. This meta-analysis suggests that the GSTP1 313 A > G polymorphism may contribute to genetic susceptibility to cancer in Indian population. However, larger studies and randomized clinical trial will be required to elucidate the biological and molecular mechanism of GSTP1 gene in cancer.

Anomalies in MiRNAs Machinery Gene, GEMIN-4 Variants Suggest Renal Cell Carcinoma Risk: A Small Experimental Study from North India.

GEMIN4 is a member of the GEMIN gene family which is involved in multiple pathologies including cancer. It is located on Chr17p13.3, the most notorious chromosome and a hotspot for various carcinomas. We therefore intend to find genetic variants of GEMIN4 gene associated with renal cell carcinoma risk (RCC). This study comprised 100 patients and 225 controls. Genotyping of GEMIN4 gene variants was done using Taqman® assay. The association of GEMIN4 variants and risk prediction of RCC was done by statistical analysis. Haplotype analysis was done to see the combined effect of variants on RCC. Patients carrying variant genotype, CC of GEMIN4 T/C rs7813 showed significant association whereas in case of GEMIN4 G/C rs910925 variant genotype, CC significant risk was found. GEMIN4 rs7813 T/C variant genotype, CC showed risk with smoking (p = 0.034). Our study gives a substantive support for the association between the GEMIN4 gene variants and RCC risk.

Genetic Variant Arg399Gln G>A of XRCC1 DNA Repair Gene Enhanced Cancer Risk Among Indian Population: Evidence from Meta-analysis and Trial Sequence Analyses.

The X-ray repair cross-complementation group 1 (XRCC1) gene plays an important role in base excision repair pathway. Several studies have reported contradictory results for XRCC1 exon 10 (Arg399Gln, G23990A, rs25487) gene polymorphism and cancer risk in Indian population, making it difficult to interpret them. Therefore, we have conducted a meta-analysis to evaluate the more precise association between XRCC1 exon 10 G>A gene polymorphism and risk of cancer by published studies. We searched PubMed (Medline) and Google scholar web databases to cover all studies published on association between XRCC1 exon 10 G>A gene polymorphism and cancer risk until August 2016. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to appraise the strength of association. Heterogeneity, publication bias and sensitivity analysis were also assessed. Twenty-five published studies had fulfilled the inclusion criteria comprising 4131 confirmed cancer cases and 5013 controls. When all studies were polled together, overall significant association was found between XRCC1 exon 10 G>A polymorphism and cancer risk in variant allele carrier (A vs. G: OR 1.217, 95% CI 1.056-1.402, p = 0.007), homozygous (AA vs. GG: OR 1.359, 95% CI 1.036-1.783, p = 0.027), dominant (AA+AG vs. GG OR 1.208, 95% CI 1.006-1.450, p = 0.043) and recessive (AA vs. AG+GG: OR 1.315, 95% CI 1.029-1.680, p = 0.029) genetic models. Further sensitivity analysis supported the stability of our result by showing similar ORs before and after removal of a single study. The present meta-analysis suggested that the XRCC1 exon 10 G>A polymorphism contribute cancer risk in Indian population, and supports that individuals with risk allele A and AA genotype are at higher risk of developing cancer.

Pepsinogen-II 100 bp ins/del gene polymorphism and its elevated circulating levels are associated with gastric cancer, particularly with Helicobacter pylori infection and intestinal metaplasia.

BACKGROUND: Polymorphism in the gene of pepsinogen-II (PG-II) and its serum level are effective biomarkers for terminal differentiation of gastric mucosa into gastritis, intestinal metaplasia (IM), and gastric cancer (GC) in relationship to Helicobacter pylori infection. METHODS: Genotyping of the PG-II 100 bp insertion/deletion (ins/del) polymorphism was performed in patients with GC (n = 192) and age- and gender-matched H. pylori-associated dyspepsia (n = 180) and healthy subjects (HS, n = 240) by PCR. IgG anti-H. pylori (in all subjects) and serum PG-II levels were estimated in 145 patients each with GC and dyspepsia and in 65 healthy controls (HC) using ELISA (Biohit Oyj, Finland). RESULTS: Five alleles were amplified by PCR: allele 5 (510 bp), allele 4 (480 bp), allele 3 (450 bp), allele 2 (400 bp), and allele 1 (shorter allele, 310 bp). Allele 1 carriage was infrequent, and serum PG-II level was higher among patients with GC than in HC [OR 0.43 (95 % CI, 0.29-0.85), p < 0.001 and mean ± SD; 17.53 ± 12.60 vs. 12.77 ± 7.53 µg/l, p = 0.005, respectively], particularly in the presence of H. pylori [OR 0.42 (0.25-0.71), p = 0.001 and 18.78 ± 12.63 vs. 13.97 ± 8.14, p = 0.034]. However, allele 1 carriage and PG-II levels were comparable among patients with GC and dyspepsia. Patients with IM also carried allele 1 infrequently and had higher levels of PG-II than those without [OR 0.5 (0.29-0.85), p = 0.011 and 20.07 ± 14.22 vs. 16.61 ± 12.08, p = 0.048]. CONCLUSIONS: Carriage of the shorter allele of the PG-II 100 bp ins/del polymorphism and elevated levels of PG-II are associated with GC, particularly with H. pylori infection and IM.

Death receptor 4 variants enhanced prostate cancer risk in North Indian population.

Death receptor 4 (DR4) is a tumor suppressor gene and plays an important mediator of apoptosis. Polymorphism in DR4 gene may reduce apoptotic capacity and provoke proliferation of cell and cancer. We evaluated genetic polymorphisms of DR4 gene in association with risk of prostate cancer (PCa) in Northern Indian population. We have recruited 192 PCa patients and 225 cancer-free ages matched unrelated healthy control of similar ethnicity. They were genotyped for DR4, 141 (G > A), 209 (C > G), and 228 (A > C) polymorphisms using amplification refractory mutation system (ARMS) method. Variant genotype AA (OR = 2.54; p = 0.007) and A allele (OR = 1.51; p = 0.015) of DR4 141 demonstrated significant increased risk for PCa. Similarly, variant genotype GG (OR = 2.58; p = 0.003) and G allele carrier (CG + GG) (OR = 1.50; p = 0.043) of DR4 209 conferred increased risk. G allele (OR = 1.50, p = 0.005) was also statistically associated with PCa risk. High risk for PCa was also observed with respect to haplotypes A-G-A (OR = 2.86; Bonferroni correction Pc = 0.008) and A-G-C (OR = 3.18, Pc = 0.008). We observed significantly enhanced risk for PCa due to interaction between DR4 209 and 228 gene polymorphisms. Furthermore, a significantly increased risk of high Gleason grade tumor was found in the combined variant allele carrier (GA + AA) of DR4 141 compared with the GG genotype (OR = 2.27, Pc = 0.052). Interaction of smoking and genotypes did not further modulate the risk of PCa. Our observations suggested that genetic variants of the DR4 gene significantly influence the risk of PCa in North Indian population and might be involved in the etiology of PCa.

Relationship of MTHFR and NQO1 Pharmacogenetics and Chemotherapy Clinical Outcomes in Breast Cancer Patients.

The study aimed at evaluating the influence of MTHFR 677C>T and NQO1 609C>T polymorphisms in toxicity and response to chemotherapy in breast cancer patients. These two genes are involved in the folate homeostasis and bioactivation of chemotherapeutic drugs, respectively. In this study, 243 patients treated with FEC/FAC/methotrexate chemotherapy regimen were recruited and followed up for toxicity (NCI-CTCAE ver. 3). While out of 243 patients, 115 patients who received neo-adjuvant chemotherapy (NACT) were followed for treatment response. Genetic analysis of MTHFR 677C>T and NQO1 609C>T was done by PCR-restriction fragment length polymorphism. We found significant association of variant genotype (TT) of NQO1 609C>T with grade 2-4 toxicity [OR 0.33 (0.13-0.88), P = 0.027] and with grade 2-4 anemia [OR 0.34 (0.12-0.95), P = 0.041]. However, no association of MTHFR 677C>T was seen with either response to NACT or drug-induced toxicity. The study provides useful information for prediction of clinical outcomes in breast cancer patients in terms of NQO1 609C>T by evaluating its association with chemotherapy-induced toxicity.

Genetic variants of NQO1 gene increase bladder cancer risk in Indian population and meta-analysis.

NAD(P)H: quinone oxidoreductase (NQO1) is cytosolic enzymes that plays a role in protection against natural and xenobiotic quinones. This enzyme also protects cells from oxidative damage by preventing the generation of reactive oxygen species and reducing environmental carcinogens. The study included 200 bladder cancer (BC) patients and 200 healthy control individuals that had been matched by age and sex, and were of similar ethnicity. NQO1 Exon 4 (C > T) and Exon 6 (C > T) gene polymorphisms were genotyped by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP). We also performed a meta-analysis of 12 studies including the present study (2,286 cases and 2,294 controls) for NQO1 Exon 6 (C > T) polymorphism and overall BC susceptibility. Variant genotype TT of NQO1 Exon 6 (C > T) demonstrated a significant risk with BC (OR = 2.54; p = 0.016). T allele carriers (CT + TT) (OR = 1.60; p = 0.020) of NQO1 Exon 6, as well as T allele (OR = 1.60; p = 0.004) were at higher risk of BC. The diplotype C-T was observed to be associated with a significant increase BC risk (Bonferroni corrected p value, Pc = 0.02; OR = 1.61). In addition, a meta-analysis of the Exon 6 (C > T) polymorphism and BC risk showed that the variant of NQO1 Exon 6 genotypes was associated with an overall increased risk of BC, which was consistent with the results of the present study. However, none of these two polymorphisms were associated with tobacco smoking, tumor progression, and risk of BC recurrence in patients treated with BCG immunotherapy. Our results suggested that the NQO1 Exon 6 (C > T) may be associated with BC risk and could be a useful marker for primary prevention and development of BC in Indian population. Larger studies are required to validate these findings in diverse populations and of different ethnicities.

No Association of Matrix Metalloproteinase [MMP]-2 (-735C > T) and Tissue Inhibitor of Metalloproteinase [TIMP]-2 (-418G > C) Gene Polymorphisms with Cervical Cancer Susceptibility.

Matrix metalloproteinase [MMP]-2 and tissue inhibitor of metalloproteinase [TIMP]-2 are emerging as pivotal players in inflammation and carcinogenesis. The present study aimed to evaluate the role of MMP-2 (-735C > T) [rs 2285053] and TIMP-2 (-418G > C) [rs 8179090] gene polymorphisms in cervical cancer susceptibility in Indian women. We recruited 200 cervical cancer patients from North India and 200 unrelated, age-matched, cancer-free healthy female controls of similar ethnicity. Genomic DNA extraction from peripheral blood samples, collected from the study subjects, was carried out using salting-out method. MMP-2 and TIMP-2 genotyping was performed using polymerase chain reaction-based restriction fragment length polymorphism. Our findings demonstrated no significant association between MMP-2 (-735C > T) and TIMP-2 (-418G > C) gene polymorphisms and the risk of developing cervical cancer in the study population. Further stratified analysis using a case-only study approach revealed that there was no effect of MMP-2/TIMP-2 polymorphisms on early and advanced stages of cervical cancer. Further MMP-2 and TIMP-2 polymorphisms did not modulate the risk in cervical cancer patients who smoked tobacco/cigarettes. Overall, the present study demonstrated a lack of association between MMP-2 and TIMP-2 gene polymorphisms and cervical cancer susceptibility in women of Northern India.

Association studies of Toll-like receptor gene polymorphisms with allograft survival in renal transplant recipients of North India.

Organ transplantation itself inevitably activates the innate immune system by Toll-like receptors (TLRs), potentially leading to allograft rejection and graft failure. We evaluated the possible association of TLR2, TLR3, and TLR9 polymorphisms of donor-recipient pairs and acute rejection in renal transplant patients of North India. TLR2 (-196 to -174 del), TLR3 (c.1377C/T; rs 3775290), and TLR9 (+2848 G/A; rs 352140) were genotyped using DNA samples from 200 donor-recipient pairs of live donor kidney transplantation by applying Restriction Fragment Length Polymorphism (RFLP) methodology. The variant allele frequency of TLR2 (-196 to -174 del) was significantly different between recipients and donors (7.5% vs. 5.0%; p = 0.049; OR = 3.9; 95% CI = 1.01-15.32). However, no significant association for allograft rejection was observed in transplant recipients for TLR3 and TLR9. Interestingly, a low prevalence of AA genotype of TLR9 + 2848 G>A was observed in rejecters when compared with non-rejecters, demonstrating protective association with allograft rejection (OR = 0.30, 95% CI = 0.12-0.88, p = 0.028). An allele in patients was also observed to be associated with higher rejection-free survival (log-rank = 0.044). These TLR gene polymorphisms, upon further evaluation, may be helpful in elucidation of immunobiological mechanisms associated with renal graft rejection.

Genetic variants in metabolizing genes NQO1, NQO2, MTHFR and risk of prostate cancer: a study from North India.

Quinone oxidoreductases (NAD(P)H): quinone oxidoreductase 1 (NQO1) and NRH: quinone oxidoreductase 2 (NQO2) are an antioxidant enzyme, important in the detoxification of environmental carcinogens. Methylene-tetra-hydrofolate reductase (MTHFR), plays a role in folate metabolism and may have oncogenic role through disruption of normal DNA methylation pattern, synthesis, and impaired DNA repair. In a case-control study, genotyping was done in 195 PCa and 250 age matched unrelated healthy controls of similar ethnicity to determine variants in NQO1 exon 4 (C > T, rs4986998), exon 6 (C > T, rs1800566), NQO2 -3423 (G > A, rs2070999) and MTHFR exon 4 (C > T, rs1801133) by PCR-RFLP methods. Heterozygous genotype CT and variant allele career genotype (CT + TT) of NQO1 exon 4 showed increased risk of PCa (OR = 2.06, p = 0.033; OR = 2.02, p = 0.027). Variant allele T also revealed increased risk (OR = 1.87, p = 0.029). Similarly variant genotype TT (OR = 2.71, p = 0.009), combined genotype (CT + TT) (OR = 1.59, p = 0.019) and T allele (OR = 1.63, p = 0.002) of NQO1 exon 6 demonstrated significant risk for PCa. Diplotypes of NQO1 (exon 4 and 6), C-T (OR = 1.56, Pc = 0.007) and T-T (OR = 0.011, Pc = 3.86) was associated with an increased risk for PCa. NQO2 and MTHFR did not show any risk with PCa. Our results strongly support that common sequence variants and diplotypes of NQO1 exon 4 and 6 genes may have role in PCa risk in the North Indian population, indicating the importance of genes involved in metabolism with respect to PCa risk. Additional studies on larger populations are needed to clarify the role of variation in these genes in PCa carcinogenesis.

Association of Toll-like receptor (TLR) 2, 3 and 9 genes polymorphism with prostate cancer risk in North Indian population.

Prostate cancer (PCa) is the most common cancer among men. It has been suggested that toll like receptors (TLRs) may contribute to PCa pathogenesis by stimulating prostate epithelial cell proliferation in response to infectious stimuli. We performed case control study to analyze the genetic variants of TLR2, 3 and 9 gene polymorphisms with PCa risk in a North Indian population. For this study we genotyped age matched, unrelated 195 PCa patients and 250 healthy controls of similar ethnicity in a case-control study. They were genotyped for TLR2 (-196 to -174 Del), TLR3 (c.1377C/T) [rs3775290] and TLR9 (G2848A) [rs352140] gene polymorphisms using polymerase chain reaction and restriction fragment length polymorphism method. Variant allele Del (D) carriers i.e. (ID + DD) of TLR2 (-196 to -174 Del) SNP, demonstrated 1.57 fold increased risk (p = 0.040; OR = 1.57, 95% CI = 1.02-2.24) as compared to Ins (I) allele, suggesting a dominant effect model involved in the risk of this polymorphism in PCa. However, variants of TLR3 and 9 gene polymorphisms were not associated with PCa risk. Our results suggested the low penetrance variant of TLR2 (-196 to -174 Del) to be at increased PCa risk in North Indian population. Functional studies in ethnically diverse populations may provide a more comprehensive involvement of innate immunity in identifying the disease-associated variants for PCa etiology.

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.

Genetic variation in microRNA genes and prostate cancer risk in North Indian population.

Recent evidence indicates the involvement of microRNAs (miRNAs), in cell growth control, differentiation, and apoptosis, thus playing a role in tumorigenesis. Single-nucleotide polymorphisms (SNPs) located at miRNA-binding sites (miRNA-binding SNPs) are likely to affect the expression of the miRNA target and may contribute to the susceptibility of humans to common diseases. We genotyped SNPs hsa-mir196a2 (rs11614913), hsa-mir146a (rs2910164), and hsa-mir499 (rs3746444) in a case-control study including 159 prostate cancer patients and 230 matched controls. Patients with heterozygous genotype in hsa-mir196a2 and hsa-mir499, showed significant risk for developing prostate cancer (P = 0.01; OR = 1.70 and P ≤ 0.001; OR = 2.27, respectively). Similarly, the variant allele carrier was also associated with prostate cancer, (P = 0.01; OR = 1.66 and P ≤ 0.001; OR = 1.97, respectively) whereas, hsa-mir146a revealed no association in prostate cancer. None of the miRNA polymorphisms were associated with Gleason grade and bone metastasis. This is the first study on Indian population substantially presenting that individual as well as combined genotypes of miRNA-related variants may be used to predict the risk of prostate cancer and may be useful for identifying patients at high risk.

Role of MMP-3 and MMP-9 and their haplotypes in risk of bladder cancer in North Indian cohort.

PURPOSE: Matrix metalloproteinases (MMPs) play critical roles in cancer development and progression. Nonsynonymous single nucleotide polymorphisms (SNPs) in functional domain of MMP-3 and MMP-9 contribute appreciably to cancer predisposition and aggression. To test this proposition we examined whether six SNPs of the MMP-3 and MMP-9 genes are associated with risk of bladder cancer (BC) in a North Indian population. METHODS: Six SNPs of MMP-3 and MMP-9 were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in a case-control study including 200 BC patients and 200 age/gender/ethnicity-matched controls. RESULTS: Increased risk for BC susceptibility was observed in MMP-3 (1171) 5A/5A [P = 0.022; odds ratio (OR), 3.46; 95% confidence interval (CI), 1.20-9.98], MMP-9 (Q279R) QQ (P = 0.048; OR, 1.92; 95%CI, 1.01-3.66), MMP-9 (P574R) PR (P < 0.001; OR, 2.62; 95%CI, 1.71-4.03) and PR + RR (P < 0.001; OR, 2.59; 95%CI, 1.72-3.91) genotypes, and in R allele (P < 0.001; OR, 2.05; 95%CI, 1.47-2.85). Furthermore, significant association between MMP-9 Q279R, P574R polymorphism and smoking was observed in BC risk. Haplotype analysis too revealed significant association with 5A-A-G of MMP-3 haplotype (P = 0.022; OR, 1.99; 95%CI, 1.11-3.60) and with R-R (P = 0.001; OR, 2.00; 95%CI, 1.35-2.97) and Q-R (P < 0.001; OR, 2.97; 95%CI, 1.65-5.37) of MMP-9 haplotype. Genotype 5A/6A of MMP-3-1171 showed borderline risk and high recurrence-free survival in Bacillus Calmette-Guérin (BCG)-treated non-muscle-invasive BC (NMIBC) patients (log-rank P = 0.025). CONCLUSION: Our data suggested that MMP-3-1171 5A/5A and MMP-9 (Q279R) QQ, MMP-9 (P574R) PR, PR + RR, and R allele are associated with high risk of BC.

Caspase 8 gene variants in healthy North Indian population and comparison with worldwide ethnic group variations.

BACKGROUND: Many strategies are being used for the quest for the disease causing genes. Inter-individual variations in several genes exist. Thus, even if they share the same disease-associated allele, the genomic backgrounds - and hence potential interacting alleles at other loci - of people with different regional ancestries may differ, with a consequent variation in the severity of their disease. MATERIALS AND METHOD: The present study was conducted to determine the distribution of Caspase 8 IVS12-19G/A, Caspase 8D302H, Caspase 8 -652del and Caspase 8 -678del polymorphisms (as frequency distribution of caspases in Indians generally is not yet known), which was then compared with different populations globally. Polymerase chain reaction (PCR)-based analysis was conducted in 205 normal healthy individuals of similar ethnicity. RESULTS: The variant allele frequencies were 17.6% (A) in Caspase 8 IVS12-19G/A, 13.2% (H) in Caspase 8D302H, 23.2% (Del) in Caspase 8 -652del and 24.6% (Del) in Caspase 8 -678del. Further, comparison of frequency distribution of these genes was done with various published studies of different ethnic groups globally. CONCLUSION: It is anticipated from our results that the frequency of these caspase genes exhibits distinctive patterns in India, which could perhaps be attributed to ethnic variation. This study is important as it can form a baseline for screening individuals who are at high risk due to exposure to environmental carcinogens and cancer predisposition, and therefore, might help in investigating linked polymorphisms in a way that will not obscure potential associations between genotype and phenotype.

Genotypic and functional roles of IL-1B and IL-1RN on the risk of gastroesophageal reflux disease: the presence of IL-1B-511*T/IL-1RN*1 (T1) haplotype may protect against the disease.

OBJECTIVES: We aimed at evaluating the role of interleukin-1B (IL-1B) and IL-1RN polymorphisms, which may modulate the gastric mucosal expression of IL-1beta, thus altering acid secretion, which influences the severity of gastroesphageal reflux disease (GERD). METHODS: In a prospective study, 144 patients with GERD (diagnosed by at least two of these criteria: Carlsson-Dent score of 6, endoscopic evidence of GERD, histopathological evidence of esophagitis, percentage time esophageal pH <4 for >5% on 24-h pH monitoring, and response to omeprazole 20 mg/day) and 368 healthy controls were genotyped for IL-1B-511 C/T and IL-1RN VNTR polymorphism (by PCR-restriction fragment length polymorphism (RFLP) and PCR, respectively). Gastric mucosal IL-1beta levels (picogram/milligram of biopsy sample) were measured (using enzyme-linked immunosorbent assay (ELISA)) in 71 patients. Helicobacter pylori diagnosis was conducted using anti-H. pylori immunoglobulin G (IgG) ELISA. RESULTS: Patients (41.1+/-13.3 years old, 96 (66.7%) men) were comparable with healthy controls (43.4+/-11.8 years old, 238 (64.7%) men) with respect to age and gender. The IL-1B-511 CC genotype and C allele were associated with higher risk of GERD than the TT genotype (P=0.01, odds ratio (OR)=2.0, 95% confidence interval (CI)=1.12-3.57) and the T allele (P=0.04, OR=1.3, 95% CI=1.0-1.7), respectively. TT and C noncarriers had more IL-1beta than CT (33.2 (2.6-161.3) vs. 16.7 (2.8-121.9), P=0.04) and C carriers (33.2 (2.6-161.3) vs. 15.16 (1.5-121.9), P=0.04), respectively. IL-1RN "1,2" and "2 carriers" had higher risk (P<0.001, OR=2.0, 95% CI=1.31-3.1; P=0.01, OR=1.6, 95% CI=1.1-2.4, respectively). "2,2" Had lower IL-1beta levels than both "1,1" and "1,2" (9.2 (1.5-70.7) vs. 26.8 (5.7-161.3), P=0.006; 9.2 (1.5-70.7) vs. 24.4 (2.6-78.0), P=0.02). However, "2 carriers" tended to have lower IL-1beta levels than "2 noncarriers" (21.7 (1.5-78.0) vs. 26.8 (5.7-161.3), P=0.09). The IL-1B-511*T/IL-1RN*1 ("T1") haplotype showed lower risk (P=0.05, OR=0.7, 95% CI=0.5-1.0). "T1" had higher IL-1beta levels than both "T1 carriers" and "T1 noncarriers" (43.5 (18.2-161.3) vs. 23.9 (2.6-121.9), P=0.02; 43.5 (18.2-161.3) vs. 10.9 (1.5-82.6), P=0.06, respectively). The presence of H. pylori infection was associated with the stronger risk of the IL-1B-511*CC genotype. The "T1" haplotype was strongly protective against GERD among patients with H. pylori infection. CONCLUSIONS: The T1 haplotype was associated with the reduced risk of GERD, particularly among patients with H. pylori infection, probably because of higher gastric mucosal IL-1beta levels.

Association of tumour necrosis factor-alpha gene (T-1031C, C-863A, and C-857T) polymorphisms with bladder cancer susceptibility and outcome after bacille Calmette-Guérin immunotherapy.

OBJECTIVE: To investigate the association of tumour necrosis factor-alpha gene (TNF-alpha) polymorphisms T-1031C, C-863A, and C-857T with bladder cancer risk and recurrence after bacille Calmette-Guérin (BCG) immunotherapy, as TNF-alpha regulates inflammatory process influencing bladder cancer susceptibility and outcome of BCG immunotherapy. PATIENTS AND METHODS: In all, 220 patients with bladder cancer and 206 controls were recruited. Genotyping was done using allele specific-polymerase chain reaction. RESULTS: A T-1031C, CC genotype and haplotype -1031C/-863C/-857T showed enhanced susceptibility to bladder cancer, with an odds ratio (OR) of 2.23 and 95% confidence interval (CI) of 1.17-4.26; and an OR of 6.05 and 95%CI of 2.46-14.90, respectively. A T-1031C, CC genotype had a reduced risk of recurrence after BCG treatment (hazard ratio 0.38, 95%CI 0.14-0.98). CONCLUSION: The present data suggests that T-1031C (CC) genotype and C/C/T haplotype may confer risk for bladder cancer, moreover T-1031C (CC) decreased the risk of recurrence after BCG immunotherapy.

IL-10 -1082 G>A: a risk for prostate cancer but may be protective against progression of prostate cancer in North Indian cohort.

BACKGROUND: Chronic intraprostatic inflammation is suspected to play a major role in the pathogenesis of prostate cancer (PCa). Polymorphisms in interleukin-10 (IL-10), a key anti-inflammatory cytokine gene can influence immune response and immune evasion of tumor cells. Its role as an anti-metastatic molecule is also well documented. METHODS: Gene promoter polymorphisms in IL-10 (-1082 G>A and -819 C>T) was analyzed in 159 PCa patients and 259 healthy controls to investigate their potential association with susceptibility for PCa. RESULTS: Our results indicated that the heterozygous (GA) and homozygous mutant (AA) genotypes of IL-10 -1082 to be more prevalent among PCa patients in comparison to controls (GA: OR - 2.8, p = 0.011; AA: OR - 2.3, p = 0.037). More patients (92.5%) than controls (82.7%) were positive for the A allele (GA + AA: OR - 2.6, p = 0.015). We observed lower frequency of T(-819)-G(-1082) haplotype in patients without bone metastasis (4.4%, OR - 0.30, p = 0.019) in comparison to PCa patients with bone metastasis (12.6%). CONCLUSION: Our results support the emerging hypothesis that genetically determined immune activity may play a role in the pathophysiology of PCa. Our findings of high producer of IL-10 -1082 variants suggest initiation of PCa. Future studies in large cohort of different ethnicity PCa groups are warranted to establish definite associations with other cytokine gene polymorphisms.

Influence of genetic polymorphisms in GSTM1, GSTM3, GSTT1 and GSTP1 on allograft outcome in renal transplant recipients.

INTRODUCTION: Glutathione S-transferases (GSTs) are important in protection against xenobiotic compounds and toxicity caused by immunosuppressants in renal transplant recipients. In the present study we hypothesize that genetic variability in GSTM1, GSTM3, GSTP1 and GSTT1 genes may be associated with allograft outcome. METHODS: The study included 223 controls and 273 transplant recipients categorized into 184 stable graft function (SGF), 57 rejection episodes (RE) and 32 delayed graft function (DGF). The polymorphism was studied using multiplex PCR and PCR-RFLP. RESULTS: GSTM1 null genotype showed a 3.35-fold higher risk for rejection in SGF vs. RE category [95% confidence interval (CI) 1.27-8.84, p = 0.014]. Mutant (G) allele of GSTP1 was associated with a 5.52-fold risk for DGF (95% CI 1.37-22.17, p = 0.016). Kaplan-Meier analysis revealed significantly lower mean time to first RE in null genotype as compared with GSTM1 present patients (Log p = 0.002). The dose adjusted C(2) levels in null genotype was higher as compared with GSTM1 present patients at one (p = 0.007) and three months (p = 0.027) post transplantation. CONCLUSION: Patients with variant genotype of GSTM1 and GSTP1 were at higher risk for rejection and delayed functioning of the allograft, respectively, supporting the hypothesis for involvement of GST isoform variants in allograft outcome in renal transplant recipients.

Cytokine gene polymorphisms are associated with risk of urinary bladder cancer and recurrence after BCG immunotherapy.

The association of interleukin-1beta (IL-1B) -511C > T and IL-1 receptor antagonist (IL-1RN) VNTR, transforming growth factor-beta (TGF-B1) +28C > T and interferon-gamma (IFN-G) + 874T>A polymorphisms with bladder cancer (CaB) susceptibility and risk of recurrence in Bacillus Calmette-Guérin (BCG)-treated patients was analyzed in 287 controls and 213 CaB patients (73 BCG treated). Increased risk was observed with the IL-1RN*2 allele (odds ratio (OR) 5.01) and the IFN-G +874 A allele (OR 1.78). TGF-B TT and IFN-G +874 A carriers were associated with reduced (hazard ratio (HR) 0.37) and enhanced (HR 2.24) risk of recurrence after BCG immunotherapy, respectively. The study suggests that cytokine gene variants may modulate CaB susceptibility and risk of recurrence after BCG immunotherapy.