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.

Keywords: Strong Heart Family Study; arsenic metabolism; arsenic species; linkage analysis; toxicogenetics; toxicokinetics.

FIG. 1.

Multipoint LOD scores for logit-transformed %iAs: overall, and from center-stratified analyses. Black line represents the multipoint LOD score from the combined analysis. Tangerine line is Arizona-restricted analysis, green line is Oklahoma-restricted analysis, and gray line is North or South Dakota-restricted analysis. Adjusted for age, age squared, sex, linear, and quadratic interactions between age and sex, study center (Arizona, Oklahoma, and North or South Dakota), obesity (body mass index ≥30 kg/m²), high-school completion (education ≥12 years), smoking status (ever/never), drinking status (current abstainer yes/no), and higher than median iAs exposure (measured by the sum of inorganic and methylated arsenic species in urine).

FIG. 2.

Multipoint LOD scores for logit-transformed %MMA: overall, and from center-stratified analyses. Black line represents the multipoint LOD score from the combined analysis. Tangerine line is Arizona-restricted analysis, green line is Oklahoma-restricted analysis, and gray line is North or South Dakota-restricted analysis. Adjusted for age, age squared, sex, linear and quadratic interactions between age and sex, study center (Arizona, Oklahoma, and North or South Dakota), obesity (body mass index ≥30 kg/m²), high-school completion (education ≥12 years), smoking status (ever/never), drinking status (current abstainer yes/no), and higher than median iAs exposure (measured by the sum of inorganic and methylated arsenic species in urine).

FIG. 3.

Multipoint LOD scores for logit-transformed %DMA: overall, and from center-stratified analyses. Black line represents the multipoint LOD score from the combined analysis. Tangerine line is Arizona-restricted analysis, green line is Oklahoma-restricted analysis, and gray line is North or South Dakota-restricted analysis. Adjusted for age, age squared, sex, linear and quadratic interactions between age and sex, study center (Arizona, Oklahoma, and North or South Dakota), obesity (body mass index ≥30 kg/m²), high-school completion (education ≥12 years), smoking status (ever/never), drinking status (current abstainer yes/no), and higher than median iAs exposure (measured by the sum of inorganic and methylated arsenic species in urine).

FIG. 4.

Multipoint LOD scores signal for principal components of the logit-transformed % arsenic species. Red line is the first principal component and orange line is the second principal component. Adjusted for age, age squared, sex, linear, and quadratic interactions between age and sex, study center (Arizona, Oklahoma, and North or South Dakota), obesity (body mass index ≥30 kg/m²), high-school completion (education ≥12 years), smoking status (ever/never), drinking status (current abstainer yes/no), and higher than median iAs exposure (measured by the sum of inorganic and methylated arsenic species in urine).

FIG. 5.

Evidence from conditional linkage analysis for QTL on chromosome 10. Outcomes: purple line is logit-transformed %iAs, blue line is logit-transformed %MMA, black line is logit-transformed %DMA, and red line is principal component #1. Covariates: solid lines show results from models adjusted for age, age squared, sex, linear, and quadratic interactions between age and sex, study center (Arizona, Oklahoma, and North or South Dakota), obesity (body mass index ≥30 kg/m²), high-school completion (education ≥12 years), smoking status (ever/never), drinking status (current abstainer yes/no), and higher than median iAs exposure (measured by the sum of inorganic and methylated arsenic species in urine). Dashed lines show further adjustment for rs17878846 and rs10509760 genotypes.