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

• Published in: Environmental health perspectives Vol. 129; no. 4; p. 47007
• Main 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
• Format: Journal Article
• Language: English
• Published: United States National Institute of Environmental Health Sciences 01-04-2021; Environmental Health Perspectives
• Subjects: Age composition; Alleles; Arsenic; Cacodylic Acid; Cardiovascular disease; Cohort analysis; Dimethylarsinic acid; DNA methylation; DNA sequencing; Drinking water; Gene frequency; Genetic diversity; Longitudinal Studies; Metabolism; Metabolites; Methyltransferase; Methyltransferases - genetics; Native North Americans; Polymorphism, Single Nucleotide; Population structure; Population studies; Proteins; Skin; Skin cancer; Toxicity; Urine; United States > US; New Hampshire
• ISSN: 0091-6765; 1552-9924; 1552-9924
• DOI: 10.1289/EHP8152

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.