rs1041449 (TMPRSS2): Prostate Cancer Risk Variant

Key takeaways

• rs1041449 is located in TMPRSS2, a gene studied in the context of prostate cancer susceptibility in a large multi-ancestry genome-wide analysis
• The supporting study examined 87,040 individuals (43,303 prostate cancer cases and 43,737 controls) across European, African, Japanese, and Latino ancestries
• The 23 newly identified risk regions from this study, combined with 76 previously known prostate cancer risk variants, together account for roughly one-third of the disease's tendency to run in families in populations of European ancestry
• In tibial artery tissue, this variant is linked to reduced expression of LINC00479, a non-coding RNA gene located nearby

What the research says A meta-analysis of more than 10 million genetic variants was conducted across 43,303 prostate cancer cases and 43,737 controls (total n=87,040) spanning populations of European, African, Japanese, and Latino ancestry. The study identified 23 novel prostate cancer susceptibility loci at genome-wide significance (P<5x10^-8); these newly identified variants, combined with 76 previously known prostate cancer risk variants, together account for approximately 33% of the familial clustering of prostate cancer in European ancestry populations. Separately, gene-expression data from GTEx v11 (953 donors) indicates that the alternate allele at this locus is associated with reduced expression of the nearby LINC00479 in tibial artery tissue GTEx Portal.

Reported associations

• Prostate cancer susceptibility: Examined within a large multi-ancestry GWAS meta-analysis of 87,040 individuals (43,303 cases, 43,737 controls) spanning European, African, Japanese, and Latino ancestries; the study identified 23 novel risk loci at genome-wide significance (P<5x10^-8)
• LINC00479 expression in tibial artery tissue: The alternate allele is associated with reduced expression of the nearby LINC00479 gene specifically in tibial artery tissue (p=5.1x10^-5, GTEx v11, 953 donors) GTEx Portal

Evidence quality The prostate cancer evidence derives from a large-scale GWAS meta-analysis of 87,040 participants across four ancestral groups, using a genome-wide significance threshold of P<5x10^-8 and imputation against the 1000 Genomes Project reference panel. Of the 23 novel variants discovered across the full study, 15 were confirmed by direct genotyping or sequencing across multiple contributing studies (imputation information r2 range: 0.76-1). Some loci showed evidence of effect heterogeneity across ancestral populations, with a subset of the novel associations appearing stronger in specific ancestry groups. The specific odds ratio or p-value for rs1041449 individually is not reported in the available study excerpts, which limits direct assessment of its standalone contribution to risk. The LINC00479 expression association in tibial artery tissue meets FDR<0.05 in GTEx v11 data across 953 donors, but represents a mechanistic signal on gene regulation and should not be interpreted as a clinical outcome GTEx Portal.

Tissue-specific expression effects

• LINC00479: The alternate allele is associated with reduced expression of this non-coding RNA gene in tibial artery tissue; no other tissues with significant expression effects were included in the provided GTEx data GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.