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The rs10993994 in the proximal MSMB promoter region is a functional polymorphism in Asian Indian subjects.

ABSTRACT: BACKGROUND:The microseminoprotein gene encoding prostate secretory protein of 94 amino acids (PSP94) harbours a potential risk allele (rs10993994) for prostate cancer (PCa) in its promoter region. However, studies on rs10993994 have been sparse in Asian Indians. METHODS:The present study recruited a sample population of 44 benign prostatic hyperplasia patients, 33 PCa patients and 60 healthy participants, of which, participants without other confounding risk factors for PCa were retained. The serum PSP94 (sPSP94) levels were measured by a serum-based ELISA in an earlier study. A novel RFLP technique was developed to screen for rs10993994 which was validated with direct sequencing. RESULTS:Sequencing showed additional 4 SNPs (rs41274660, rs141211965, rs12770171, rs10669586) and 2 novel variants (GenBank accession nos. KM265191 and KM265192). In silico DNA topographical studies predicted that KM265192 would have higher cleavage intensity and more accessibility for binding of transcription factors. Even though, similar frequencies were observed for all the variants in all the three study groups, the risk allele 'T' (rs10993994) was seen to be associated with reduced PSP94 expression both at mRNA and protein level. Further, mRNA expression as studied by real-time PCR correlated positively with sPSP94 levels. Interestingly, CC genotype of rs10993994 showed highest sPSP94 levels in all the three study groups and was associated with Gleason score ?7 in PCa patients. In contrast, TT genotype of rs10993994 was associated with lesser sPSP94 levels and with aggressiveness of PCa. CONCLUSION:rs10993994 was found to be a functional SNP in the studied Asian Indian population.

SUBMITTER: Mhatre DR

PROVIDER: S-EPMC4516150 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A single nucleotide polymorphism (SNP) rs2853669 (A>G) in the telomerase reverse transcriptase (TERT) promoter has recently been reported in chr5:1,295,349 T>C (T349C), and was shown to be associated with increased cancer risk and poor survival in a specific population. However, at present, the role of this particular SNP with TERT promoter driver mutations and its genetic association with human papilloma virus (HPV) in patients with cervical cancer has not been determined. In the present study, the genetic association of the functional SNP rs2853669 in the presence/absence of TERT promoter hotspot mutations and HPV in patients with cervical cancer of South Indian origin was evaluated. To understand and compare the frequency of the variant allele and its risk association in different cancer types of various populations, the SNP was genotyped in 257 cervical cancer samples and 295 controls, and its associations with TERT promoter hotspot mutations and HPV were analyzed. Furthermore, an extensive search of previously published articles in PubMed, Embase and Web of Science was conducted; a meta-analysis was carried out to elucidate the association of the SNP with different cancer types in global populations. The SNP analysis showed significantly high frequency (41%) of homozygous variant allele rs2853669 (GG) in patients with cervical cancer compared with control samples [Recessive allele model odds ratio (OR)=1.71; 95% CI=1.20-2.43; P=0.003]. No significant interaction was observed between the TERT SNP rs2853669 and HPV status as well as other hotspot TERT promoter (C228T and C250T) mutations determined in our previous study. In addition, the overall meta-analysis revealed a significant association of the SNP rs2853669 with other cancer types in different ethnic populations (OR=1.09; 95% CI=1.03-1.16; P=0.004). The present results suggested that the TERT SNP rs2853669 could play an important role in the risk of cervical cancer in a South Indian population.

Project description:Our previous studies have implicated genes mainly involved in the activity of pancreatic ? cells in type 2 diabetes (T2D) susceptibility in the North Indian population. Recent literature on the role of SIRT1 as a potential master switch modulating insulin secretion and regulating gene expression in pancreatic ? cells has warranted an evaluation of SIRT1 promoter region polymorphisms in the North Indian population, which is the main focus of the present study. 1542 samples (692 T2D patients and 850 controls) were sequenced for the 1.46 kb region upstream the translation start site of the SIRT1 gene. We performed a functional characterization of the SIRT1 promoter region polymorphisms using luciferase assay and observed a single-nucleotide polymorphism (SNP), rs12778366, in association with SIRT1 expression. We propose that TT, the high-expressing genotype of SNP rs12778366 in the SIRT1 promoter region and present in >80% of the North Indian population, was favored under conditions of feast-famine cycles in evolution, which has turned out to be a cause of concern in the present sedentary lifestyle under ad libitum conditions. Case-control association analysis did not implicate rs12778366 in T2DM per se in the studied population. However, our earlier reported risk genotype combinations of mt-ND3, PGC1?, and UCP2-866, when compared with the protective genotype combinations, in the background of the high-expressing TT genotype of SIRT1 SNP rs12778366, showed a very high additive risk [corrected odd ratio (OR)?=?8.91; p?=?6.5×10(-11)]. The risk level was considerably low in the genotype backgrounds of TX (OR?=?6.68; p?=?2.71×10(-12)) and CX (OR?=?3.74; p?=?4.0×10(-3)). In addition, we screened other reported T2D-associated polymorphisms: PIK3R1 rs3730089, IRS1 rs1801278, and PPP1R3 rs1799999, which did not show any significant association in North Indian population. The present paper emphasizes the importance of gene interactions in the biological pathways of T2D, a complex lifestyle disease.

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The rs10993994 in the proximal MSMB promoter region is a functional polymorphism in Asian Indian subjects.

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