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 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.

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.

Polymorphisms and haplotypes in caspases 8 and 9 genes and risk for prostate cancer: a case-control study in cohort of North India.

OBJECTIVE: Despite the potential importance of apoptosis pathways in prostate tumor etiology, little has been published regarding prostate tumor risk associated with common gene variants in caspases (CASP). Normal variations within the sequence of apoptotic genes may lead to suboptimal apoptotic capacity and therefore increased cancer risk. MATERIALS AND METHODS: Using data from a hospital-based case-control study conducted by Sanjay Gandhi Post Graduate Institute of Medical Science, India, from 2007 to 2009, we evaluated risk of prostate cancer (CaP) in 165 patients and age-matched 205 healthy controls. We genotyped the functional IVS12-19G/A, D302H, -678del, and -652 6N ins/del polymorphisms in the promoter of CASP 8 and -293del, -1263A/G in CASP 9 genes. RESULTS: A significant increased risk for CaP was found for the CASP 8 IVS12-19G/A heterozygous genotype (P = 0.02; OR = 1.69) as well as for the variant allele carriers (P = 0.04; OR = 1.56). Also the CASP 9 -1263A/G showed lower risk for both heterozygous and variant allele carrier genotypes (P = 0.002; OR = 0.45 and P = 0.05; OR = 0.66 respectively). CASP 9 -1263A/G was also found to be associated with increased risk with bone metastasis. Furthermore, a significant additive interaction between CASP 8 IVS12-19G/A polymorphism and tobacco smoking was observed with CaP risk. CONCLUSION: These results suggested that the CASP 8 IVS12-19G/A and CASP 9 -1263 polymorphism may be involved in etiology of CaP and thus could be implicated as a marker for genetic susceptibility in North Indian population.

Genetic polymorphisms in MHC-encoded antigen processing gene TAP2: a case-control study in end-stage renal disease patients of North India.

AIM: TAP2 genes are involved in antigen presentation by MHC class I molecules, especially in the transport of endogenous peptides. As for most MHC genes, a polymorphism has been described and the possibility that it could influence the recipient immune response by modulating antigen presentation in renal disorders. The aim of our study was to analyze TAP2 gene polymorphism in between ESRD (end stage renal disease) patients and healthy controls in our North Indian population. MATERIALS AND METHOD: We analyzed 3 polymorphisms in the TAP2 gene viz. 565 (G→A, Ala→Thr), 379 (G→A, Val→Ile) and 665 (A→G, Thr→Ala), by amplification refractory mutation system-polymerase chain reaction, (ARMS-PCR) methodology using SPSS 11.0 (Chicago, IL, U.S.A.) in a hospital based case-control study in 148 ESRD cases and 230 healthy controls. They were age and sex matched and were of similar ethnicity. RESULTS: Our results showed that only TAP2 G>A 379 Val/Ile was found to be significant for end stage renal disease patients. Furthermore, 2 haplotypes, Ile(379)-Thr(665) and Ile(379)-Ala(665) (p=0.001; OR=0.28 and p=0.030; OR=4.30 respectively) were also associated with the disease and on the other hand gene combination effect revealed protective pattern with ESRD (Val/Ile(379)-Thr/Thr(665) p=0.007; OR=0.30). These results suggested that the currently described polymorphism in the limited coding region of TAP2 genes individually does not influence end stage renal disease risk. It however, proposes a strong link when in combination with each other. CONCLUSION: The study suggests that the possibility exists that some alleles, in the TAP genes, might confer susceptibility or protection in patients with ESRD which might prove to be helpful in identifying individuals at a higher risk for progressive renal insufficiency.

Impact of total and ionized serum calcium on prostate cancer risk in North Indian men.

INTRODUCTION: Calcium has anti-proliferative and pro-differentiation effects on cells in vitro and can inhibit the development of various cancers. While there is some epidemiologic evidence for an inverse relation between dietary calcium intake and prostate cancer risk, only few have focused on serum calcium levels in this respect. MATERIALS AND METHODS: We assayed total serum calcium and ionized serum calcium in a pilot study of 40 prostate cancer patients and compared with 40 healthy controls. RESULTS: Our observations provided evidence for an association between prostate cancer risk and total and ionized serum calcium levels(p=0.020 and p≤0.001 respectively). The mean difference of total serum calcium was also significant in patients with serum PSA >20ng/ ml (p=0.017). CONCLUSION: This is an important and interesting finding which requires further exploration into mechanism involved in calcium channel and prostate cancer risk in a larger cohort of different ethnic population.

Investigative role of pre-microRNAs in bladder cancer patients: a case-control study in North India.

MicroRNAs (miRNA) are a class of small noncoding RNA molecules that have been implicated in a wide variety of cellular functions through post-transcriptional regulations on target genes. Common genetic variants (single-nucleotide polymorphisms, SNPs) in pre-miRNA genes may alter their expression and/or maturation effecting thousands of target mRNAs, resulting in varied functional consequences. Three common SNPs (hsa-mir-146a G>C rs2910164, hsa-mir-196a2 C>T rs11614913, and hsa-mir-499 T>C rs3746444) in pre-miRNAs were investigated to evaluate their association with urinary bladder cancer risk. The hospital-based case-control study comprised of 212 histologically confirmed patients with urinary bladder cancer and 250 healthy controls who were unrelated, of similar ethnicity, and age and gender matched. Genotyping was done using polymerase chain reaction-restriction fragment length polymorphism methodology. Our results showed that the heterozygous genotype of rs11614913 was higher in cases than controls but the results were marginally significant (p = 0.055; odds ratio, 1.44). Smoking had no impact in modulating the effect of any of the three miRNA SNPs studied. No association was observed with either the tumor stage or grade in patients with bladder cancer. Even though there was no association between the individuals carrying the variant genotypes of the three miRNA studied and bladder cancer risk, marginal significance of heterozygousity in rs11614913 suggested further characterization of miRNA SNPs in a large cohort of varied ethnicity. This could further provide new prospects for understanding the underlying mechanisms between miRNAs and disease etiology.

Role of functional polymorphisms of P53 and P73 genes with the risk of prostate cancer in a case-control study from Northern India.

BACKGROUND AND AIMS: P53 gene variants BstUI RFLP at codon 72 in exon 4, 16-bp tandem repeat in intron 3 and Msp I RFLP in intron 6 and P73 gene variants of G4C14-to-A4T14 (GC/AT), exon 2 polymorphism, which respectively codes for four functionally different protein isoforms, have been shown to modulate susceptibility to different types of human neoplasms. We undertook this study to evaluate the role of P53 and P73 SNPs in prostate cancer in a Northern Indian population. METHODS: P53 and P73 genotypes were assessed in a hospital-based case-control study comprised of 177 prostate cancer cases and 265 healthy controls. After the extraction of genomic DNA from blood, genotyping was done using PCR-RFLP and PCR-CTPP methods, respectively. RESULTS: A significant association was found in P53 intron 6 G>A and P53 R72P G>C polymorphism with PCa risk. In P53 intron 6 G>A polymorphism the heterozygous genotype (GA) showed marginal risk with the disease (OR = 1.48, 95% CI = 0.999-2.220). Individuals with heterozygous genotype only (GC) of P53 R72P G>C polymorphism demonstrated PCa risk (OR = 1.5, 95% CI = 1-2.199). Haplotypes G-C-D and A-G-D (OR = 1.58, 95% CI = 1.125-2.241 and OR = 2.70, 95% CI = 1.767-4.143, respectively) were also found to be associated with an increased risk of PCa. CONCLUSIONS: Our study provided evidence that the P53 intron 6 G>A and R72P G>C polymorphisms were associated with a higher risk of prostate cancer in a Northern Indian population.