Rare, protein-altering variants in as3mt and arsenic metabolism efficiency: A multi-population association study

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, n = 2,434 ), Strong Heart Study (SHS, n = 868 ), and New Hampshire Skin Cancer Study (NHSCS, n = 666 ). We assessed the collective effects of rare (allele frequency < 1 % ), protein-altering AS3MT 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).

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 [ β = - 9.4 (95% CI: - 13.9 , - 4.8 )], SHS [ β = - 6.9 (95% CI: - 13.6 , - 0.2 )], and NHSCS [ β = - 8.7 (95% CI: - 15.6 , - 2.2 )]. In meta-analyses across cohorts, DMA% was 8.7% lower in carriers [ β = - 8.7 (95% CI: - 11.9 , - 5.4 )].

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.