{"doi":"10.1289/ehp8152","title":"Rare, Protein-Altering Variants in <i>AS3MT</i> and Arsenic Metabolism Efficiency: A Multi-Population Association Study","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, 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 [b = -9:4 (95% CI: -13:9, -4:8)], SHS [b = -6:9 (95% CI: -13:6, -0:2)], and NHSCS [b = -8:7 (95% CI: -15:6, -2:2)]. In meta-analyses across cohorts, DMA% was 8.7% lower in carriers [b = -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.","journal":"Environmental Health Perspectives","year":2021,"id":189868,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":226933,"name":"Meytal Chernoff","orcid":"0000-0003-2704-8912","position":1,"is_corresponding":false},{"id":753262,"name":"Lei Huang","orcid":"0000-0002-5337-9101","position":2,"is_corresponding":false},{"id":614298,"name":"Tong Lin","orcid":"0009-0009-3132-2356","position":3,"is_corresponding":false},{"id":753263,"name":"Lin Chen","orcid":"0000-0001-5905-7368","position":4,"is_corresponding":false},{"id":29386,"name":"Farzana Jasmine","orcid":"0000-0002-5980-1174","position":5,"is_corresponding":false},{"id":229555,"name":"Justin Shinkle","orcid":null,"position":6,"is_corresponding":false},{"id":246476,"name":"Shelley A. Cole","orcid":"0000-0002-2651-0127","position":7,"is_corresponding":false},{"id":532081,"name":"Karin Haack","orcid":"0000-0003-3067-3575","position":8,"is_corresponding":false},{"id":579328,"name":"Jack W. Kent","orcid":"0000-0002-0758-7639","position":9,"is_corresponding":false},{"id":390060,"name":"Jason G. Umans","orcid":"0000-0002-2746-3350","position":10,"is_corresponding":false},{"id":78639,"name":"Lyle G. Best","orcid":"0000-0002-7813-0724","position":11,"is_corresponding":false},{"id":48173,"name":"HEATHER H. NELSON","orcid":"0000-0003-1901-9513","position":12,"is_corresponding":false},{"id":310680,"name":"Donald J. Vander Griend","orcid":"0000-0003-4421-5698","position":13,"is_corresponding":false},{"id":425143,"name":"Joseph H. Graziano","orcid":null,"position":14,"is_corresponding":false},{"id":29387,"name":"Muhammad G. Kibriya","orcid":"0000-0001-9784-6958","position":15,"is_corresponding":false},{"id":288772,"name":"Ana Navas‐Acién","orcid":"0000-0001-9824-7797","position":16,"is_corresponding":false},{"id":48177,"name":"MARGARET R. KARAGAS","orcid":"0000-0002-6398-7362","position":17,"is_corresponding":false},{"id":226942,"name":"Habibul Ahsan","orcid":"0000-0001-9808-377X","position":18,"is_corresponding":false},{"id":108967,"name":"Brandon L. Pierce","orcid":"0000-0002-7829-952X","position":19,"is_corresponding":false},{"id":226935,"name":"Dayana Delgado","orcid":"0009-0009-3480-3155","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-18T23:49:22.671571Z","pmid":"33826413","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}