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

Maria Tellez-Plaza,^1,2,3,4 Matthew O. Gribble,^1,2 V. Saroja Voruganti,⁵ Kevin A. Francesconi,⁶ Walter Goessler,⁶ Jason G. Umans,^7,8 Ellen K. Silbergeld,² Eliseo Guallar,^1,3,9,10 Nora Franceschini,¹¹ Kari E. North,¹¹ Wen H. Kao,^1,9 Jean W. MacCluer,⁵ Shelley A. Cole,⁵ and Ana Navas-Acien^1,2,9,10

¹Department of Epidemiology, and ²Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA; ³Area of Epidemiology and Population Genetics, National Center for Cardiovascular Research (CNIC), Madrid, Spain; ⁴Fundacion de Investigacion del Hospital Clinico de Valencia-INCLIVA, Valencia, Spain; ⁵Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, USA; ⁶Institute of Chemistry–Analytical Chemistry, Karl-Franzens University, Graz, Austria; ⁷MedStar Health Research Institute, Hyattsville, Maryland, USA; ⁸Georgetown–Howard Universities Center for Clinical and Translational Science, Washington, DC, USA; ⁹Welch Center for Prevention, Epidemiology and Clinical Research, and ¹⁰Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA; ¹¹Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

Abstract

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.

Key words: American Indians, arsenic metabolism, arsenic species, determinants, heritability, linkage scan, Strong Heart Study.

Environ Health Perspect 121:345–351 (2013). http://dx.doi.org/10.1289/ehp.1205305 [Online 15 January 2013]

Address correspondence to A. Navas-Acien, Departments of Environmental Health Sciences and Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe St., Room W7513D, Baltimore, MD 21205 USA. Telephone: (410) 502-4267. E-mail: anavas@jhsph.edu

Supplemental Material is available online (http://dx.doi.org/10.1289/ehp.1205305).

This work was supported by grants from the National Heart, Lung, and Blood Institute (NHLBI) (R01HL090863), the Strong Heart Study (HL41642, HL41652, HL41654 and HL65520), and the National Institute of Environmental Health Sciences (R01ES021367 and P30ES03819). M.T.-P.was supported by a Rio Hortega training grant (Funds for Research in Health Sciences, Ministry of Science and Innovation, Spain). M.G. was supported by a T32 training grant from the NHLBI (5T32HL007024). This study was conducted in part in facilities constructed with support from the National Center for Research Resources (C06 RR13556 and C06 RR017515).

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

Received 4 April 2012; Accepted 14 January 2013; Online 15 January 2013.