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

Paulina Gomez-Rubio, Maria M. Meza-Montenegro, Ernesto Cantu-Soto, Walter Klimecki

Research output: Contribution to journalArticle

35 Citations (Scopus)

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 r2 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.

Original languageEnglish (US)
Pages (from-to)260-270
Number of pages11
JournalJournal of Applied Toxicology
Volume30
Issue number3
DOIs
StatePublished - Apr 2010

Fingerprint

Chromosomes, Human, Pair 10
Methylation
Linkage Disequilibrium
Arsenic
Chromosomes
Association reactions
Metabolism
Polymorphism
Genes
Single Nucleotide Polymorphism
Nucleotides
Disease Susceptibility
Methyltransferases
Mexico

Keywords

  • Arsenic
  • AS3MT
  • Linkage disequilibrium
  • Polymorphism
  • SNP

ASJC Scopus subject areas

  • Toxicology

Cite this

Genetic association between intronic variants in AS3MT and arsenic methylation efficiency is focused on a large linkage disequilibrium cluster in chromosome 10. / Gomez-Rubio, Paulina; Meza-Montenegro, Maria M.; Cantu-Soto, Ernesto; Klimecki, Walter.

In: Journal of Applied Toxicology, Vol. 30, No. 3, 04.2010, p. 260-270.

Research output: Contribution to journalArticle

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