title: Linkage Analysis of Urine Arsenic Species Patterns in the Strong Heart Family Study.
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.
authors.affiliation: *Department of Preventive Medicine, University of Southern California, Los Angeles, California; mgribble@usc.edu.
authors.forename: Matthew O
authors.initials: MO
authors.lastname: Gribble
authors.affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina; UNC Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina;
authors.forename: Venkata Saroja
authors.initials: VS
authors.lastname: Voruganti
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas;
authors.forename: Shelley A
authors.initials: SA
authors.lastname: Cole
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas;
authors.forename: Karin
authors.initials: K
authors.lastname: Haack
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland; Department of Epidemiology, Johns Hopkins Medical Institutions, Baltimore, Maryland;
authors.forename: Poojitha
authors.initials: P
authors.lastname: Balakrishnan
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Health Science Center, San Antonio-Regional Academic Health Center, Brownsville, Texas;
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Laston
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland; Biomedical Research Institute, Hospital Clinic de Valencia-INCLIVA, Valencia, Spain;
authors.forename: Maria
authors.initials: M
authors.lastname: Tellez-Plaza
authors.affiliation: Institute of Chemistry-Analytical Chemistry, University of Graz, Graz, Austria;
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Francesconi
authors.affiliation: Institute of Chemistry-Analytical Chemistry, University of Graz, Graz, Austria;
authors.forename: Walter
authors.initials: W
authors.lastname: Goessler
authors.affiliation: Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, District of Columbia; MedStar Health Research Institute, Hyattsville, Maryland;
authors.forename: Jason G
authors.initials: JG
authors.lastname: Umans
authors.affiliation: *Department of Preventive Medicine, University of Southern California, Los Angeles, California;
authors.forename: Duncan C
authors.initials: DC
authors.lastname: Thomas
authors.affiliation: *Department of Preventive Medicine, University of Southern California, Los Angeles, California;
authors.forename: Frank
authors.initials: F
authors.lastname: Gilliland
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina;
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina;
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland; Department of Epidemiology, Johns Hopkins Medical Institutions, Baltimore, Maryland; Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Ana
authors.initials: A
authors.lastname: Navas-Acien
mesh_terms: D000328:Adult; D001130:Arizona; D020261:Arsenic Poisoning / Q000201:enzymology / Q000235:genetics* / Q000652:urine; D001152:Arsenicals / Q000652:urine*; D015415:Biomarkers / Q000652:urine; D001711:Biotransformation; D015331:Cohort Studies; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D018895:Microsatellite Repeats; D015146:Midwestern United States; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D066007:Toxicokinetics
chemical_list: D001152:Arsenicals; D015415:Biomarkers; D008780:Methyltransferases; C505756:AS3MT protein, human
keywords: Strong Heart Family Study; arsenic metabolism; arsenic species; linkage analysis; toxicogenetics; toxicokinetics