Association of cardiometabolic genes with arsenic metabolism biomarkers in American Indian communities: The strong heart family study (SHFS)

Poojitha Balakrishnan, Dhananjay Vaidya, Nora Franceschini, V. Saroja Voruganti, Matthew O. Gribble, Karin Haack, Sandra Laston, Jason G. Umans, Kevin A. Francesconi, Walter Goessler, Kari E. North, Elisa Lee, Joseph Yracheta, Lyle G. Best, Jean W. Maccluer, Jack Kent, Shelley A. Cole, Ana Navas-Acien

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)15-22
Number of pages8
JournalEnvironmental health perspectives
Volume125
Issue number1
DOIs
StatePublished - Jan 2017

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Health, Toxicology and Mutagenesis

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    Balakrishnan, P., Vaidya, D., Franceschini, N., Saroja Voruganti, V., Gribble, M. O., Haack, K., Laston, S., Umans, J. G., Francesconi, K. A., Goessler, W., North, K. E., Lee, E., Yracheta, J., Best, L. G., Maccluer, J. W., Kent, J., Cole, S. A., & Navas-Acien, A. (2017). Association of cardiometabolic genes with arsenic metabolism biomarkers in American Indian communities: The strong heart family study (SHFS). Environmental health perspectives, 125(1), 15-22. https://doi.org/10.1289/EHP251