Rare, Protein-Altering Variants in AS3MT and Arsenic Metabolism Efficiency: A Multi-Population Association Study

Common genetic variation in the arsenic methyltransferase ( ) 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 could have even larger effects on AME, but their contribution to AME has not been investigated. We estimated the impact of rare, protein-coding variation in on AME using a multi-population approach to facilitate the discovery of population-specific and shared causal rare variants. We generated targeted DNA sequencing data for the coding regions of for three arsenic-exposed cohorts with existing data on arsenic species measured in urine: Health Effects of Arsenic Longitudinal Study (HEALS, ), Strong Heart Study (SHS, ), and New Hampshire Skin Cancer Study (NHSCS, ). We assessed the collective effects of rare (allele frequency ), protein-altering variants on DMA%, using multiple approaches, including a test of the association between rare allele carrier status (yes/no) and DMA% using linear regression (adjusted for common variants in 10q24.32 region, age, sex, and population structure). We identified 23 carriers of rare-protein-altering 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 [ (95% CI: , )], SHS [ (95% CI: , )], and NHSCS [ (95% CI: , )]. In meta-analyses across cohorts, DMA% was 8.7% lower in carriers [ (95% CI: , )]. Rare, protein-altering variants in 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.