title: Genome-wide association study identifies chromosome 10q24.32 variants associated with arsenic metabolism and toxicity phenotypes in Bangladesh.
abstract: Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10(-8)) for percentages of both monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) near the AS3MT gene (arsenite methyltransferase; 10q24.32), with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity) and 1,794 controls, we show that one of these five variants (rs9527) is also associated with skin lesion risk (P = 0.0005). Using a subset of individuals with prospectively measured arsenic (n = 769), we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P = 0.01). Expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P = 10(-12)) and neighboring gene C10orf32 (P = 10(-44)), which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical skin lesion risk. The observed patterns of associations suggest that MMA% and DMA% have distinct genetic determinants and support the 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 worldwide.
authors.affiliation: Department of Health Studies, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Pierce
authors.forename: Muhammad G
authors.initials: MG
authors.lastname: Kibriya
authors.forename: Lin
authors.initials: L
authors.lastname: Tong
authors.forename: Farzana
authors.initials: F
authors.lastname: Jasmine
authors.forename: Maria
authors.initials: M
authors.lastname: Argos
authors.forename: Shantanu
authors.initials: S
authors.lastname: Roy
authors.forename: Rachelle
authors.initials: R
authors.lastname: Paul-Brutus
authors.forename: Ronald
authors.initials: R
authors.lastname: Rahaman
authors.forename: Muhammad
authors.initials: M
authors.lastname: Rakibuz-Zaman
authors.forename: Faruque
authors.initials: F
authors.lastname: Parvez
authors.forename: Alauddin
authors.initials: A
authors.lastname: Ahmed
authors.forename: Iftekhar
authors.initials: I
authors.lastname: Quasem
authors.forename: Samar K
authors.initials: SK
authors.lastname: Hore
authors.forename: Shafiul
authors.initials: S
authors.lastname: Alam
authors.forename: Tariqul
authors.initials: T
authors.lastname: Islam
authors.forename: Vesna
authors.initials: V
authors.lastname: Slavkovich
authors.forename: Mary V
authors.initials: MV
authors.lastname: Gamble
authors.forename: Md
authors.initials: M
authors.lastname: Yunus
authors.forename: Mahfuzar
authors.initials: M
authors.lastname: Rahman
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Graziano
authors.forename: Habibul
authors.initials: H
authors.lastname: Ahsan
mesh_terms: D001151:Arsenic / Q000378:metabolism*; D020261:Arsenic Poisoning / Q000235:genetics; D001152:Arsenicals / Q000378:metabolism; D001459:Bangladesh; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D004781:Environmental Exposure; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014874:Water Pollutants, Chemical / Q000633:toxicity
chemical_list: D001152:Arsenicals; D014874:Water Pollutants, Chemical; D001151:Arsenic