Rare, Protein-Altering Variants in AS3MT 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, ), Strong Heart Study (SHS, ), and New Hampshire Skin Cancer Study (NHSCS, ). We assessed the collective effects of rare (allele frequency ), 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 [ (95% CI: , )], SHS [ (95% CI: , )], and NHSCS [ (95% CI: , )]. In meta-analyses across cohorts, DMA% was 8.7% lower in carriers [ (95% CI: , )]. 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

Sequencing-based fine-mapping and in silico functional characterization of the 10q24.32 arsenic metabolism efficiency locus across multiple arsenic-exposed populations

“…This study builds on previous work in the 10q24.32 region [ 29 , 31 , 49 , 54 , 55 ] in several ways. Previous studies have found signs of positive selection near the AS3MT gene associated with efficient arsenic metabolism [ 56 ].…”

“…Data were analyzed using PLINK v1.9 [ 70 ] for SHS and NHSCS and using Genome-wide Complex Train Analysis (GCTA) [ 72 ] for HEALS to allow adjustment for cryptic relatedness using a genetic relationship matrix in a linear mixed model [ 28 , 31 , 54 , 72 , 73 ]. To generate this kinship matrix, we used genome-wide SNP data available for 2,434 HEALS participants.…”

“…Arsenocholine (AsC) and arsenobetaine (AsB) are nontoxic forms of (organic) arsenic and were excluded from our primary analyses. Details regarding the measurement protocols and the limit of detection for each metabolite used by each study have been described previously and can be found in S1 Text (Supplemental Methods) [17,54,58,63].…”

Mendelian randomization analysis of arsenic metabolism and pulmonary function within the Hispanic Community Health Study/Study of Latinos

“…Since arsenic metabolites were not measured in HCHS/SOL, the first assumption cannot be directly tested. However, its plausibility is supported first by the multiple study populations in which variation near the AS3MT region has convincingly been associated with iAs metabolism 15 , 17 , 18 , 74 , 75 . Additionally, the SNVs selected for the instrument belong to biological pathways that are known to be involved in arsenic metabolism efficiency.…”

Inherited genetic effects on arsenic metabolism: A comparison of effects on arsenic species measured in urine and in blood

“…11 Prior GWA studies of Bangladeshi individuals have identified independent associations of four SNPs (single nucleotide polymorphisms) with AME: three in the 10q24.32/ AS3MT region (rs4919690, rs11191492, and rs191177668) and one in the FTCD gene (rs61735836). 12,18,19 The FTCD gene plays an important role in histidine catabolism, which generates one-carbon units that can enter the one-carbon/folate cycle, which in turn provides methyl groups for arsenic metabolism. 12 All four of these SNPs are independently associated with urine DMA%.…”