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Linkage Analysis of Urine Arsenic Species Patterns in the Strong Heart Family Study.

by Umans, Jason G.
Citation: Toxicological Sciences. 148(1):89-100, 2015 Nov..Journal: Toxicological sciences : an official journal of the Society of Toxicology.Published: 2015ISSN: 1096-0929.Full author list: Gribble MO; Voruganti VS; Cole SA; Haack K; Balakrishnan P; Laston SL; Tellez-Plaza M; Francesconi KA; Goessler W; Umans JG; Thomas DC; Gilliland F; North KE; Franceschini N; Navas-Acien A.UI/PMID: 26209557.Subject(s): Adult | Arizona | Arsenic Poisoning/en [Enzymology] | *Arsenic Poisoning/ge [Genetics] | Arsenic Poisoning/ur [Urine] | *Arsenicals/ur [Urine] | Biomarkers/ur [Urine] | Biotransformation | Cohort Studies | Female | Genetic Linkage | *Genetic Predisposition to Disease | Genome-Wide Association Study | Humans | Linkage Disequilibrium | Logistic Models | Male | Methylation | *Methyltransferases/ge [Genetics] | Methyltransferases/me [Metabolism] | *Microsatellite Repeats | Midwestern United States | Polymorphism, Single Nucleotide | Principal Component Analysis | ToxicokineticsInstitution(s): MedStar Health Research InstituteActivity type: Journal Article.Medline article type(s): Journal Article | Multicenter Study | Research Support, N.I.H., Extramural | Research Support, Non-U.S. Gov'tDigital Object Identifier: http://dx.doi.org/10.1093/toxsci/kfv164 (Click here) Abbreviated citation: Toxicol Sci. 148(1):89-100, 2015 Nov.Abstract: 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 2189 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 arsenic metabolism 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 species individually. Some other loci were suggestive or significant for 1 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.Copyright © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: [email protected]

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