Association of Cardiometabolic Genes with Arsenic Metabolism Biomarkers in American Indian Communities: The Strong Heart Family Study (SHFS)

Abstract

Background:Metabolism of inorganic arsenic (iAs) is subject to inter-individual variability, which is explained partly by genetic determinants.Objectives:We investigated the association of genetic variants with arsenic species and principal components of arsenic species in the Strong Heart Family Study (SHFS).Methods:We examined variants previously associated with cardiometabolic traits (~ 200,000 from Illumina Cardio MetaboChip) or arsenic metabolism and toxicity (670) among 2,428 American Indian participants in the SHFS. Urine arsenic species were measured by high performance liquid chromatography–inductively coupled plasma mass spectrometry (HPLC-ICP-MS), and percent arsenic species [iAs, monomethylarsonate (MMA), and dimethylarsinate (DMA), divided by their sum × 100] were logit transformed. We created two orthogonal principal components that summarized iAs, MMA, and DMA and were also phenotypes for genetic analyses. Linear regression was performed for each phenotype, dependent on allele dosage of the variant. Models accounted for familial relatedness and were adjusted for age, sex, total arsenic levels, and population stratification. Single nucleotide polymorphism (SNP) associations were stratified by study site and were meta-analyzed. Bonferroni correction was used to account for multiple testing.Results:Variants at 10q24 were statistically significant for all percent arsenic species and principal components of arsenic species. The index SNP for iAs%, MMA%, and DMA% (rs12768205) and for the principal components (rs3740394, rs3740393) were located near AS3MT, whose gene product catalyzes methylation of iAs to MMA and DMA. Among the candidate arsenic variant associations, functional SNPs in AS3MT and 10q24 were most significant (p < 9.33 × 10–5).Conclusions:This hypothesis-driven association study supports the role of common variants in arsenic metabolism, particularly AS3MT and 10q24.Citation:Balakrishnan P, Vaidya D, Franceschini N, Voruganti VS, Gribble MO, Haack K, Laston S, Umans JG, Francesconi KA, Goessler W, North KE, Lee E, Yracheta J, Best LG, MacCluer JW, Kent J Jr., Cole SA, Navas-Acien A. 2017. Association of cardiometabolic genes with arsenic metabolism biomarkers in American Indian communities: the Strong Heart Family Study (SHFS). Environ Health Perspect 125:15–22; http://dx.doi.org/10.1289/EHP251

Arsenic metabolism and one-carbon metabolism at low-moderate arsenic exposure: Evidence from the Strong Heart Study

“…(Chen et al 2012; Del Razo et al 2011; Kuo et al 2015; Mendez et al 2016; Nizam et al 2013; Wang et al 2007) Understanding non-modifiable (genetics, sex, life-stage) and modifiable (smoking, alcohol intake, kidney function, body mass index, nutrition) determinants of arsenic metabolism is important given the role of arsenic metabolism in arsenic toxicity. (Balakrishnan et al 2016; Council 2013; Gribble et al 2013; Jansen et al 2016)…”

Is Insulin Resistance Work Related?

“…There were also other compounds affecting the citric acid cycle or the amino acid metabolism that were specifically modified only in diabetes, supporting the influence of arsenic on the diabetes status [135]. Under moderate environmental arsenic exposure [136], high inorganic urinary As and urinary DMA excretion were associated with high diabetes incidence; higher MMA had an inverse effect. Experimental data also supports an action of DMA on adipocytes (reduction of the insulin signal) and on beta cells apoptosis.…”

Association of Low-Moderate Arsenic Exposure and Arsenic Metabolism with Incident Diabetes and Insulin Resistance in the Strong Heart Family Study

“…Urine creatinine levels were measured by an automated alkaline picrate reagent method. We studied effect modification of the associations by rs12768205 in AS3MT , the single nucleotide polymorphism (SNP) with the strongest association in a MetaboChip association analysis with iAs%, MMA%, and DMA% in the SHFS ( Balakrishnan et al 2016 ). SNP genotyping details have been previously published ( Balakrishnan et al 2016 ).…”

“…However, contrary to what has been observed for other health outcomes, lower MMA%, and higher DMA% in urine has been related to type 2 diabetes risk in adults ( Kuo et al 2015 ; Mendez et al 2016 ; Nizam et al 2013 ). Arsenic methylation is partly determined by genetic variants in AS3MT (encoding arsenic (III) methyltransferase) ( Balakrishnan et al 2016 ) and some one-carbon metabolism (OCM) nutrients ( Gamble et al 2006 ; Spratlen et al 2017 ). In particular, randomized clinical trials ( Gamble et al 2006 ) and observational studies ( Kordas et al 2016 ; Spratlen et al 2017 ) showed that supplementation and intake of folate and other OCM nutrients increased arsenic methylation capacity (decreased iAs% and increased DMA%).…”