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

Dayana A. Delgado, Meytal Chernoff, Lei Huang, Lin Tong, Lin Chen, Farzana Jasmine, Justin Shinkle, Shelley A. Cole, Karin Haack, Jack Kent, Jason Umans, Lyle G. Best, Heather Nelson, Donald Vander Griend, Joseph Graziano, Muhammad G. Kibriya, Ana Navas-Acien, Margaret R. Karagas, Habibul Ahsan, Brandon L. Pierce

Research output: Contribution to journalArticlepeer-review


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, formula presented ), Strong Heart Study (SHS, formula presented ), and New Hampshire Skin Cancer Study (NHSCS, formula presented ). We assessed the collective effects of rare (allele frequency formula presented ), 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 [formula presented (95% CI: formula presented )], SHS [formula presented (95% CI: formula presented )], and NHSCS [formula presented (95% CI: formula presented )]. In meta-analyses across cohorts, DMA% was 8.7% lower in carriers [formula presented (95% CI: formula presented )]. 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.

Original languageEnglish (US)
Pages (from-to)47007
Number of pages1
JournalEnvironmental health perspectives
Issue number4
StatePublished - Apr 1 2021

PubMed: MeSH publication types

  • Journal Article

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