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Rare, Protein-Altering Variants in AS3MT and Arsenic Metabolism Efficiency: A Multi-Population Association Study.
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- Author(s): Delgado, Dayana A.; Chernoff, Meytal; Lei Huang; Lin Tong; Lin Chen; 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.
- Source:
Environmental Health Perspectives. Apr2021, Vol. 129 Issue 4, p047007-1-047007-11. 11p. 1 Diagram, 4 Charts, 1 Graph. - Source:
- Additional Information
- Subject Terms:
- 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, 푛 = 2,434), Strong Heart Study (SHS, 푛 = 868), and New Hampshire Skin Cancer Study (NHSCS, 푛 = 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 [ß=-9.4 (95% CI: -13.9, -4.8)], SHS [ß=-6.9 (95% CI: -13.6, -0.2)], and NHSCS [ß=-8.7 (95% CI: -15.6, -2.2)]. In meta-analyses across cohorts, DMA% was 8.7% lower in carriers [ß=-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. [ABSTRACT FROM AUTHOR]
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