Linkage Analysis of Urine Arsenic Species Patterns in the Strong Heart Family Study.
Linkage Analysis of Urine Arsenic Species Patterns in the Strong Heart Family Study.
- 2015
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].
English
1096-0929
*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
Toxicokinetics
MedStar Health Research Institute
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
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].
English
1096-0929
*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
Toxicokinetics
MedStar Health Research Institute
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't