Abstract 4443: Trans-population two-sample Mendelian randomization study of circulating metabolites and prostate cancer risk

Abstract While prostate cancer (PCa) is highly heritable, mechanisms underlying disease risk and PCa disparities are not well understood. Here, we conducted a two-sample Mendelian randomization (MR) to assess whether serum metabolites are causally associated with PCa risk in European, African, and Hispanic populations. MR analyses were performed on metabolite quantitative trait loci (mQTLs) for 250 metabolites quantified by untargeted mass spectroscopy via the Metabolon platform for 1,498 European and 1,740 African ancestry individuals from the Atherosclerosis Risk in Communities (ARIC) cohort and for 711 metabolites measured in 3,166 Hispanic individuals from the Hispanic Community Health Study/Study of Latinos (SOL). PCa GWAS summary statistics were obtained for men from European (122,188 cases, 604,640 controls), African (19,391 cases, 61,608 controls) and Hispanic (3,931 cases, 26,405 controls) populations from the PRACTICAL Consortium. Within each population, QTLs associated with metabolites at the genome-wide significance level (P<5x10-8) were included in instruments upon removing rare (minor allele frequency≤0.01) or correlated (R2≥0.2) SNPs calculated in ancestry-matched TOPMed populations. Inverse variance weighted (IVW) random effect models are presented as primary results. Sensitivity analyses were utilized to assess assumption violations (weighted mode, weighted median and MR egger). MR were conducted separately in each population, and fixed effect meta-analyses were conducted across population-specific MR results to identify trans-population associations. A false discovery rate was implemented to account for multiple testing. In total, 22, 4 and 1 metabolites significantly associated with PCa risk in Hispanic, European and African populations, respectively. Of these, 13 metabolites had a MR instrument in ≥1 population, 12 of which were significant following a trans-population meta-analysis, including 5 fatty acids, 3 lysophospholipids, 1 amino acid, 1 carbohydrate, 1 nucleotide and 1 xenobiotic. All fatty acids were associated with decreased PCa odds (2%-10%), as were 4 other metabolites (amino acid 3-methyoxytyrosine, nucleotide 5-methyluridine and lysophospholipids 1-archidonoyl-GPC (20:4n6) and 1-archidonoyl-GPE (20:4n6), 4%-9%). The 3 remaining metabolites, erythritol, 1-linoleoyl-GPE (18:2) and mannose, were found to increase PCa odds by 10%, 6% and 4%, respectively. Additional metabolite harmonization efforts are underway to conduct trans-population analyses metabolome-wide. This study provides evidence of associations between metabolites, such as fatty acids and lysophysopholipids, and PCa across diverse populations. These findings point to mechanisms that could inform preventive or therapeutic strategies pending functional investigations. Multivariable and bidirectional MR are ongoing to further assess findings. Citation Format: Harriett Fuller, Rebecca Rohde, Heather Highland, Jiayi Shen, Bing Yu, Eric Boerwinkle, Megan Grove, Kari E. North, David V. Conti, Christopher A. Haiman, Kristin Young, Burcu Darst. Trans-population two-sample Mendelian randomization study of circulating metabolites and prostate cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4443.