TY  - BOOK
AU  - Umans, Jason G
TI  - Linkage Analysis of Urine Arsenic Species Patterns in the Strong Heart Family Study
SN  - 1096-0929
PY  - 2015///
KW  - *Arsenic Poisoning/ge [Genetics]
KW  - *Arsenicals/ur [Urine]
KW  - *Genetic Predisposition to Disease
KW  - *Methyltransferases/ge [Genetics]
KW  - *Microsatellite Repeats
KW  - Adult
KW  - Arizona
KW  - Arsenic Poisoning/en [Enzymology]
KW  - Arsenic Poisoning/ur [Urine]
KW  - Biomarkers/ur [Urine]
KW  - Biotransformation
KW  - Cohort Studies
KW  - Female
KW  - Genetic Linkage
KW  - Genome-Wide Association Study
KW  - Humans
KW  - Linkage Disequilibrium
KW  - Logistic Models
KW  - Male
KW  - Methylation
KW  - Methyltransferases/me [Metabolism]
KW  - Midwestern United States
KW  - Polymorphism, Single Nucleotide
KW  - Principal Component Analysis
KW  - Toxicokinetics
KW  - MedStar Health Research Institute
KW  - Journal Article
KW  - Multicenter Study
KW  - Research Support, N.I.H., Extramural
KW  - Research Support, Non-U.S. Gov't
N2  - 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: journals.permissions@oup.com
UR  - http://dx.doi.org/10.1093/toxsci/kfv164
ER  -