ClinVar Genomic variation as it relates to human health

In a large 2-stage genomewide association study of prostate cancer, Thomas et al. (2008) identified a single-nucleotide polymorphism, rs10993994, in the proximal promoter of the MSMB gene that was significantly associated with prostate cancer risk (HPC13; 611928) (7.31 x 10(-13)). Eeles et al. (2008) conducted a genomewide association study using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at or before the age of 60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA; see 176820) concentration (less than 0.5 ng/ml). They analyzed these samples for 541,129 SNPs. Eeles et al. (2008) identified a SNP in the MSMB gene, rs10993994, that was significantly associated with prostate cancer (8.7 x 10(-29)). The SNP rs10993994 is 2 basepairs upstream of the transcription start site of MSMB. The risk allele, T, affects multiple predicted binding sites for transcription and splicing factors. Chang et al. (2009) genotyped 16 tagging SNPs and imputed 29 additional SNPs in a 65-kb genomic region at chromosome 10q11 in a Swedish population-based case-control study including 2,899 cases and 1,722 controls. They found evidence for 2 independent loci, separated by a recombination hotspot, associated with prostate cancer risk. Among multiple significant SNPs at locus 1, the initial SNP, rs10993994, was the most significant. The risk allele of this SNP, T, had only 13% of the promoter activity of the wildtype allele in a prostate cancer model, LNCaP cells. Chang et al. (2009) concluded that the T allele of rs10993994 may be a potential causal variant at chromosome 10q11 that confers increased risk of prostate cancer. By fine-mapping analysis of a 65-kb region on chromosome 10q including rs10993994 in 6,118 prostate cancer cases and 6,105 controls of European origin, Lou et al. (2009) found that rs10993994 remained the SNP most strongly associated with prostate cancer risk (p = 8.8 x 10(-18); heterozygous odds ratio (OR) of 1.20, homozygous OR of 1.64). Lou et al. (2009) stated that the SNP was located at position -57. In vitro functional analysis showed that the T allele was associated with decreased transcriptional activity and that the C allele preferentially bound to the CREB transcription factor (123810). Analysis of tumor cell lines with a CC or CT genotype revealed a higher level of MSMB gene expression compared to cell lines with a TT genotype. Lou et al. (2009) suggested that regulation of MSMB expression is a plausible mechanism accounting for the association with prostate cancer identified at this locus. Yeager et al. (2009) sequenced a 97-kb region of chromosome 10q11.2 including the area surrounding the MSMB gene and the NCOA4 gene (601984) in 70 unrelated individuals, including 36 with prostate cancer. They identified a 51-kb block of linkage disequilibrium (LD) containing rs10993994 and the proximal promoter of the MSMB gene. No additional variants in LD with rs10993994 were identified, suggesting that this is the probable variant that accounts for the association with prostate cancer. In total, 241 novel polymorphisms were identified in the 97-kb region, but none were in the exons of the MSMB gene. No polymorphic sites were found in the first 6 exons of the NCOA4 gene, but several were observed in exons 7 through 10. (less)