Title: Rare, Protein-Altering Variants in AS3MT and Arsenic Metabolism Efficiency: A Multi-Population Association Study.
Authors: Delgado, Dayana A; Chernoff, Meytal; Huang, Lei; Tong, Lin; Chen, Lin; Jasmine, Farzana; Shinkle, Justin; Cole, Shelley A; Haack, Karin; Kent, Jack; Umans, Jason; Best, Lyle G; Nelson, Heather; Griend, Donald Vander; Graziano, Joseph; Kibriya, Muhammad G; Navas-Acien, Ana; Karagas, Margaret R; Ahsan, Habibul; Pierce, Brandon L
Published In Environ Health Perspect, (2021 04)
Abstract: BACKGROUND: Common genetic variation in the arsenic methyltransferase (AS3MT) gene region is known to be associated with arsenic metabolism efficiency (AME), measured as the percentage of dimethylarsinic acid (DMA%) in the urine. Rare, protein-altering variants in AS3MT could have even larger effects on AME, but their contribution to AME has not been investigated. OBJECTIVES: We estimated the impact of rare, protein-coding variation in AS3MT on AME using a multi-population approach to facilitate the discovery of population-specific and shared causal rare variants. METHODS: We generated targeted DNA sequencing data for the coding regions of AS3MT for three arsenic-exposed cohorts with existing data on arsenic species measured in urine: Health Effects of Arsenic Longitudinal Study (HEALS, RESULTS: We identified 23 carriers of rare-protein-altering AS3MT variant across all cohorts (13 in HEALS and 5 in both SHS and NHSCS), including 6 carriers of predicted loss-of-function variants. DMA% was 6-10% lower in carriers compared with noncarriers in HEALS [ DISCUSSION: Rare, protein-altering variants in AS3MT were associated with lower mean DMA%, an indicator of reduced AME. Although a small percentage of the population (0.5-0.7%) carry these variants, they are associated with a 6-10% decrease in DMA% that is consistent across multiple ancestral and environmental backgrounds. https://doi.org/10.1289/EHP8152.
PubMed ID: 33826413
MeSH Terms: Arsenic*; Cacodylic Acid; Longitudinal Studies; Methyltransferases/genetics; Polymorphism, Single Nucleotide