Abstract 2925: Genome-wide association study identifies 10q24.32 variants associated with arsenic metabolism and premalignant skin lesion risk in Bangladesh

Abstract

Abstract Arsenic is a class-I human carcinogen, and arsenic contamination of drinking water is a serious public health issue in many countries, increasing risk for a wide array of diseases, including cancers of the bladder, kidney, lung, and skin. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity, however the basis of this variation in not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related phenotypes to identify genetic determinants of arsenic metabolism and gene-arsenic interactions influencing risk for arsenic-induced premalignant skin lesions (a classical sign of arsenic toxicity). Using data on urinary arsenic metabolite concentrations and genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5x10^-8) for urinary concentrations of both monomethylarsonic (MMA) and dimethylarsinic (DMA) in a large linkage disequilibrium block containing the AS3MT gene (arsenite methyltransferase; 10q24.32), with five genetic variants showing strong evidence independent association. In a follow-up analysis of 1,085 individuals with premalignant skin lesions and 1,794 controls population-based, we show that one of these five variants (rs9527, which is associated with DMA%) is associated with arsenical skin lesion risk (P=0.0005). Using a subset of individuals with prospectively measured arsenic metabolites (n=769), we show that rs9527 interacts with arsenic exposure to influence skin lesion risk (P=0.01). The direction of the observed association is consistent with the prevailing hypothesis that DMA is the less toxic than MMA. To evaluate the functional role of the five identified SNPs, we conducted expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individual's lymphocyte RNA. Our results suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P=10^-12) or neighboring gene C10orf32 (P=10^-44). This is an intriguing finding in part because C10orf32 and AS3MT are known to be involved in read-through transcription, producing a transcript that is presumed to be non-functional. To our knowledge, this is the largest genetic association study of arsenic metabolites to date, the only GWAS of arsenic-related traits, and the first to implicate 10q24.32 variants in both arsenic metabolism and arsenical skin lesion risk. Our results suggest that MMA% and DMA% have distinct genetic determinants and support hypothesis that DMA is the less toxic of these two methylated arsenic species. These results have potential translational implications for the prevention and treatment of arsenic-associated toxicities, including several types of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2925. doi:1538-7445.AM2012-2925