Abstract 4726: Genetic determinants of serum retinol: A genome-wide association study

Abstract

Abstract Background: Retinol, the most biologically active form of vitamin A, is hypothesized to influence a wide range of diseases. We recently reported results from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study suggesting that higher serum retinol is related to increased prostate cancer risk. Circulating retinol concentrations are influenced by many factors in addition to dietary and supplemental intake, including those related to intestinal absorption, transport, and cleavage of pro-vitamin A compounds to form retinol. Thus, genetic factors that influence retinol concentrations may also impact human disease risk. Methods: We conducted a genome-wide association study (GWAS) of 4,041 Caucasian individuals drawn from two cohorts: the ATBC Study and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Our findings were replicated in an independent sample of 2,056 individuals from the Nurses’ Health Study. Results: We identified two independent SNPs near the genes encoding key retinol carrier proteins, transthyretin (TTR) and retinol binding protein 4 (RBP4), that were associated at the level of genome-wide significance with retinol concentrations: rs1667255 (in 18q12.1) and rs10882272 (in 10q23.33). After meta-analysis with the replication sample, these SNPs remained highly significant (rs1667255: p = 2.33 × 10-14; rs10882272: p = 1.08 × 10-13). In the two GWAS studies, mean serum retinol concentrations increased with number of risk alleles (0,1,2) for TTR from 556-578-602 μg/L in ATBC and 654-688-711 μg/L in PLCO, and decreased for 0,1,2 risk alleles in RBP4 (580-567-541 μg/L in ATBC and 697-668-653 μg/L in PLCO). Conclusions: This is the first GWAS of circulating retinol levels to reveal novel, genome-wide significant loci, one near TTR and one near RBP4, genes that encode the two major retinol carrier proteins. Understanding the genetic and other determinants of retinol status may help shed light on the etiology of cancer and other diseases associated with vitamin A. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4726. doi:10.1158/1538-7445.AM2011-4726