Linkage Analysis of Urine Arsenic Species Patterns in the Strong Heart Family Study, Toxicol Sci. 2015 Jul 23,
Gribble MO1, Voruganti VS2, Cole SA3, Haack K3, Balakrishnan P4, Laston SL5, Tellez-Plaza M6, Francesconi KA7, Goessler W7, Umans JG8, Thomas DC9,Gilliland F9, North KE10, Franceschini N10, Navas-Acien A11.
- 1* Department of Preventive Medicine; University of Southern California; Los Angeles, CA firstname.lastname@example.org.
- 2Department of Nutrition; University of North Carolina; Chapel Hill, NC UNC Nutrition Research Institute, University of North Carolina at Chapel Hill; Kannapolis, NC.
- 3Department of Genetics; Texas Biomedical Research Institute; San Antonio, TX.
- 4Department of Environmental Health Sciences; Johns Hopkins University; Baltimore, MD Department of Epidemiology; Johns Hopkins Medical Institutions; Baltimore, MD.
- 5South Texas Diabetes and Obesity Institute, University of Texas Health Science Center, San Antonio – Regional Academic Health Center, Brownsville, Texas.
- 6Department of Environmental Health Sciences; Johns Hopkins University; Baltimore, MD Biomedical Research Institute, Hospital Clinic de Valencia – INCLIVA; Valencia, Spain.
- 7Institute of Chemistry – Analytical Chemistry; University of Graz; Graz, Austria.
- 8** Georgetown-Howard Universities Center for Clinical and Translational Science; Washington DC MedStar Health Research Institute; Hyattsville, MD.
- 9* Department of Preventive Medicine; University of Southern California; Los Angeles, CA.
- 10Department of Epidemiology; University of North Carolina; Chapel Hill, NC.
- 11Department of Environmental Health Sciences; Johns Hopkins University; Baltimore, MD Department of Epidemiology; Johns Hopkins Medical Institutions; Baltimore, MD Welch Center for Prevention, Epidemiology and Clinical Research; Johns Hopkins Medical Institutions; Baltimore, MD Department of Oncology; Johns Hopkins Medical Institutions; Baltimore, MD.
Arsenic toxicokinetics are important for disease risks in exposed populations, but genetic determinants are not fully understood.
We examined urine arsenic species patterns measured by HPLC-ICPMS among 2,189 Strong Heart Study participants 18 years of age and older with data on ~400 genome-wide microsatellite markers spaced ~10 cM and arsenic speciation (683 participants from Arizona, 684 from Oklahoma, and 822 from North and South Dakota). We logit-transformed % arsenic species (% inorganic arsenic, %MMA and %DMA) and also conducted principal component analyses of the logit % arsenic species. We used inverse-normalized residuals from multivariable-adjusted polygenic heritability analysis for multipoint variance components linkage analysis. We also examined the contribution of polymorphisms in the arsenicmetabolism gene AS3MT via conditional linkage analysis.
We localized a quantitative trait locus (QTL) on chromosome 10 (LOD 4.12 for %MMA, 4.65 for %DMA, and 4.84 for the first principal component of logit % arsenic species). This peak was partially but not fully explained by measured AS3MT variants. We also localized a QTL for the second principal component of logit % arsenic species on chromosome 5 (LOD 4.21) that was not evident from considering % arsenic speciesindividually. Some other loci were suggestive or significant for one geographical area but not overall across all areas, indicating possible locus heterogeneity.
This genome-wide linkage scan suggests genetic determinants of arsenic toxicokinetics to be identified by future fine-mapping, and illustrates the utility of principal component analysis as a novel approach that considers % arsenic species jointly.
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