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

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Citation: Toxicological Sciences. 148(1):89-100, 2015 Nov.PMID: 26209557Institution: MedStar Health Research InstituteForm of publication: Journal ArticleMedline article type(s): Journal Article | Multicenter Study | Research Support, N.I.H., Extramural | Research Support, Non-U.S. Gov'tSubject headings: *Arsenic Poisoning/ge [Genetics] | *Arsenicals/ur [Urine] | *Genetic Predisposition to Disease | *Methyltransferases/ge [Genetics] | *Microsatellite Repeats | Adult | Arizona | Arsenic Poisoning/en [Enzymology] | Arsenic Poisoning/ur [Urine] | Biomarkers/ur [Urine] | Biotransformation | Cohort Studies | Female | Genetic Linkage | Genome-Wide Association Study | Humans | Linkage Disequilibrium | Logistic Models | Male | Methylation | Methyltransferases/me [Metabolism] | Midwestern United States | Polymorphism, Single Nucleotide | Principal Component Analysis | ToxicokineticsYear: 2015ISSN:
  • 1096-0929
Name of journal: Toxicological sciences : an official journal of the Society of ToxicologyAbstract: 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].All authors: Balakrishnan P, Cole SA, Franceschini N, Francesconi KA, Gilliland F, Goessler W, Gribble MO, Haack K, Laston SL, Navas-Acien A, North KE, Tellez-Plaza M, Thomas DC, Umans JG, Voruganti VSFiscal year: FY2016Digital Object Identifier: Date added to catalog: 2016-09-07
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Journal Article MedStar Authors Catalog Article 26209557 Available 26209557

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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