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

Abstract

BackgroundThe 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.MethodsThe 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.ResultsSequencing 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.Conclusionrs10993994 was found to be a functional SNP in the studied Asian Indian population.

Structural and molecular biology of PSP94 Its significance in prostate pathophysiology

“…Nonetheless, three large functional studies show that the T allele at rs10993994 is associated with lower sPSP94 levels as compared to the C allele, in PCa cases (69) as well as healthy controls (70,71). Our study also showed the T risk allele to be associated with reduced PSP94 mRNA and protein expression, in both malignant and non-malignant cases and the rs10993994 was found to be a functional SNP in Asian Indians (64). Nevertheless, rs10993994 had been shown to be associated with both the altered sPSP94 expression and PCa risk (69,72).…”

“…Also, this SNP was not found to be a predisposing factor for BPH development (62,63). In a recent study by our group, we observed that the frequency of rs10993994 was similar in healthy participants as well as BPH and PCa patients (64). Another Asian study, which included 122 PCa patients from North India, suggested that the T risk allele was associated with risk for metastatic PCa (65).…”

“…PSP94 exists as a monomer which consists of two domains held together by the disulfide linkage between Cys37-Cys73; where the N-(residues 1-52) and Cterminal (residues 53-94) are held in close proximity via a strong hydrogen bond (106). The ten cysteine residues were found to be paired between 2 Cys-50 Cys, 18 Cys-42 Cys, 37 Cys- 73 Cys, 40 Cys-49 Cys and 64 Cys- 87 Cys (Figure 2). The disulphide alignments of beta-MSPs from different species obtained by means of different methods are compared in Table 2.…”

A genome‐wide association study of prostate cancer in Latinos

“…28,30 As found in previous studies in men of African ancestry, 16 directional consistency was also observed for the majority (>80%) of risk variants in Latinos, among which~30% were nominally statistically significant, suggesting that most of the known genetic susceptibility loci for PrCa generalize to the Latino population, which may not be surprising given their high degree of European ancestry. At 10q11.22, the risk variant rs10993994 has been consistently associated with PrCa risk across populations, [32][33][34] and is likely to be the putative causal variant within the region. The risk region at 8q24 harbors multiple independent risk variants and is consistently recognized as the most significant PrCa risk region across ethnic populations.…”

“…16,31 However, in the Latino population, the 10q11.22 surpassed 8q24 as the most significant risk region. At 10q11.22, the risk variant rs10993994 has been consistently associated with PrCa risk across populations, [32][33][34] and is likely to be the putative causal variant within the region. 35 The risk allele rs10993994-T is more common among populations of African ancestry (RAF AFR = 0.65, RAF AMR = 0.40, RAF EUR = 0.39) in Phase III 1KGP.…”