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. 2013 Mar;121(3):345-51.
doi: 10.1289/ehp.1205305. Epub 2013 Jan 15.

Heritability and Preliminary Genome-Wide Linkage Analysis of Arsenic Metabolites in Urine

Free PMC article

Heritability and Preliminary Genome-Wide Linkage Analysis of Arsenic Metabolites in Urine

Maria Tellez-Plaza et al. Environ Health Perspect. .
Free PMC article


Background: Arsenic (III) methyltransferase (AS3MT) has been related to urine arsenic metabolites in association studies. Other genes might also play roles in arsenic metabolism and excretion.

Objective: We evaluated genetic determinants of urine arsenic metabolites in American Indian adults from the Strong Heart Study (SHS).

Methods: We evaluated heritability of urine arsenic metabolites [percent inorganic arsenic (%iAs), percent monomethylarsonate (%MMA), and percent dimethylarsinate (%DMA)] in 2,907 SHS participants with urine arsenic measurements and at least one relative within the cohort. We conducted a preliminary linkage analysis in a subset of 487 participants with available genotypes on approximately 400 short tandem repeat markers using a general pedigree variance component approach for localizing quantitative trait loci (QTL).

Results: The medians (interquartile ranges) for %iAs, %MMA, and %DMA were 7.7% (5.4-10.7%), 13.6% (10.5-17.1%), and 78.4% (72.5-83.1%), respectively. The estimated heritability was 53% for %iAs, 50% for %MMA, and 59% for %DMA. After adjustment for sex, age, smoking, body mass index, alcohol consumption, region, and total urine arsenic concentrations, LOD [logarithm (to the base of 10) of the odds] scores indicated suggestive evidence for genetic linkage with QTLs influencing urine arsenic metabolites on chromosomes 5 (LOD = 2.03 for %iAs), 9 (LOD = 2.05 for %iAs and 2.10 for %MMA), and 11 (LOD = 1.94 for %iAs). A peak for %DMA on chromosome 10 within 2 Mb of AS3MT had an LOD of 1.80.

Conclusions: This population-based family study in American Indian communities supports a genetic contribution to variation in the distribution of arsenic metabolites in urine and, potentially, the involvement of genes other than AS3MT.

Conflict of interest statement

The authors declare they have no actual or potential competing financial interests.


Figure 1
Figure 1
LOD scores on chromosomes 5, 9, 10, and 11 for urine arsenic metabolites in SHS participants with STR marker genotype (n = 487). Models were adjusted for age, age2, sex, age × sex, age2 × sex, smoking status (never, former, current), education (< 12 years, ≥12 years), alcohol drinking status (never, former, current), BMI (< 30 kg/m2, ≥ 30 kg/m2), location (Arizona, Oklahoma, North and South Dakota), and total arsenic (log µg/g). Residual kurtosis was –0.14 for %iAs, %MMA, and %DMA. The number of pair relationships among the 487 participants was distributed as follows: 33 parent–offspring; 268 siblings; 93 avuncular; 36 half siblings; 2 double first cousins; 3 grand avuncular; 19 half avuncular; 87 first cousins; 9 half first cousins and half second cousins; 8 first cousins once removed (1 rem); 5 half first cousins; 6 half first cousins, 1 rem, and half second cousins, 1 rem.

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