TY - JOUR
T1 - Rare, protein-altering variants in as3mt and arsenic metabolism efficiency
T2 - A multi-population association study
AU - Delgado, Dayana A.
AU - Chernoff, Meytal
AU - Huang, Lei
AU - Tong, Lin
AU - Chen, Lin
AU - Jasmine, Farzana
AU - Shinkle, Justin
AU - Cole, Shelley A.
AU - Haack, Karin
AU - Kent, Jack
AU - Umans, Jason
AU - Best, Lyle G.
AU - Nelson, Heather
AU - Vander Griend, Donald
AU - Graziano, Joseph
AU - Kibriya, Muhammad G.
AU - Navas-Acien, Ana
AU - Karagas, Margaret R.
AU - Ahsan, Habibul
AU - Pierce, Brandon L.
N1 - Publisher Copyright:
© 2021, Public Health Services, US Dept of Health and Human Services. All rights reserved.
PY - 2021
Y1 - 2021
N2 - 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 an-cestral and environmental backgrounds.
AB - 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 an-cestral and environmental backgrounds.
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U2 - 10.1289/EHP8152
DO - 10.1289/EHP8152
M3 - Article
C2 - 33826413
AN - SCOPUS:85103998173
SN - 0091-6765
VL - 129
JO - Environmental health perspectives
JF - Environmental health perspectives
IS - 4
M1 - 047007
ER -
