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J Appl Toxicol. 2010 Apr;30(3):260-70. doi: 10.1002/jat.1492.

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

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1
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721-0207, USA.

Abstract

Differences in arsenic metabolism are known to play a role in individual variability in arsenic-induced 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 five 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.

KEYWORDS:

AS3MT; Arsenic; Linkage Disequilibrium; SNP; polymorphism

PMID:
20014157
PMCID:
PMC2862143
DOI:
10.1002/jat.1492
[Indexed for MEDLINE]
Free PMC Article
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