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.
1Department of Environmental Health Sciences, and 2Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA; 3The Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA; 4Clinical and Translational Research, Johns Hopkins School of Medicine, Baltimore, Maryland, USA; 5Department of Epidemiology, and 6Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; 7UNC Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina, USA; 8Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA; 9Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, USA; 10South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley, Brownsville, Texas, USA; 11MedStar Health Research Institute, Hyattsville, Maryland, USA; 12Georgetown and Howard Universities Center for Clinical and Translational Science, Washington, DC, USA; 13Institute of Chemistry – Analytical Chemistry, University of Graz, Austria; 14Center for American Indian Health Research, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; 15Missouri Breaks Industries Research, Inc., Timber Lake, South Dakota, USA; 16Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Recommended Citation:
Poojitha Balakrishnan,1,2,et al. Association of Cardiometabolic Genes with Arsenic Metabolism Biomarkers in American Indian Communities: The Strong Heart Family Study (SHFS)[J]. Environmental Health Perspectives,2017-01-01,Volume 125(Issue 1):15