Genetic association between intronic variants in AS3MT and arsenic methylation efficiency is focused on a large linkage disequilibrium cluster in chromosome 10

Abstract

Differences in arsenic metabolism are known to play a role in individual variability in arsenicinduced disease susceptibility. Genetic variants in genes relevant to arsenic metabolism are considered to be partially responsible for the variation in arsenic metabolism. Specifically, variants in arsenic (3+ oxidation state) methyltransferase (AS3MT), the key gene in the metabolism of arsenic, have been associated with increased arsenic methylation efficiency. Of particular interest is the fact that different studies have reported that several of the AS3MT single nucleotide polymorphisms (SNPs) are in strong linkage-disequilibrium (LD), which also extends to a nearby gene, CYP17A1. In an effort to characterize the extent of the region in LD, we genotyped 46 SNPs in a 347,000 base region of chromosome 10 that included AS3MT in arsenic-exposed subjects from Mexico. Pairwise LD analysis showed strong LD for these polymorphisms, represented by a mean r 2 of 0.82, spanning a region that includes 5 genes. Genetic association analysis with arsenic metabolism confirmed the previously observed association between AS3MT variants, including this large cluster of linked polymorphisms, and arsenic methylation efficiency. The existence of a large genomic region sharing strong LD with polymorphisms associated with arsenic metabolism presents a predicament because the observed phenotype cannot be unequivocally assigned to a single SNP or even a single gene. The results reported here should be carefully considered for future genomic association studies involving AS3MT and arsenic metabolism.

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

“…The associated genes such as AS3MT and GSTO1/2 highlight oxidative stress as a possible mechanism in arsenic biotransformation and therefore in arsenic-related diseases. Given the high LD in the 10q24 region in populations throughout the world (Fujihara et al 2010; Gomez-Rubio et al 2010), and particularly among the American Indians in our study, further investigation in comparable populations and using low-frequency variants is needed to confirm our findings. Further knowledge of causal variation may highlight biological mechanisms that are related to arsenic metabolism, including methylation, and may contribute to the elucidation of possible mechanisms for arsenic toxicity and the development of chronic diseases including skin lesions, cancer, and cardiovascular disease.…”

Arsenic exposure in Latin America: Biomarkers, risk assessments and related health effects

“…They were similarly associated with a SNP (rs743572) located near the gene CYP17A1 , 27 kbs upstream of AS3MT (Engstrom et al, 2009). Taken together, these results indicate the presence of a large haplotype block (pairwise LD analysis r 2 = 0.82) (at least 63 kbs in size, on chromosome 10) that can have a profound effect on health outcomes by altering the methylation of As (Gomez-Rubio et al, 2010). Sampayo-Reyes et al .…”

Influence of arsenate and arsenite on signal transduction pathways: an update

“…For example, in a study of a Mexican population that was exposed to arsenic in the drinking water, there were variations in arsenic methylation efficiency among individuals (Gomez-Rubio et al 2009). In another study of Bangladeshi adults whose diets were deficient in folate, it was found that variability in nutritional status may be a risk factor for arsenic toxicity (Gamble et al 2005).…”