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SLCO1B1 variants and urine arsenic metabolites in the Strong Heart Family Study.

ABSTRACT: Arsenic species patterns in urine are associated with risk for cancer and cardiovascular diseases. The organic anion transporter coded by the gene SLCO1B1 may transport arsenic species, but its association with arsenic metabolites in human urine has not yet been studied. The objective of this study is to evaluate associations of urine arsenic metabolites with variants in the candidate gene SLCO1B1 in adults from the Strong Heart Family Study. We estimated associations between % arsenic species biomarker traits and 5 single-nucleotide polymorphisms (SNPs) in the SLCO1B1 gene in 157 participants, assuming additive genetics. Linear regression models for each SNP accounted for kinships and were adjusted for sex, body mass index, and study center. The minor allele of rs1564370 was associated with lower %MMA (p = .0003) and higher %DMA (p = .0002), accounting for 8% of the variance for %MMA and 9% for %DMA. The rs1564370 minor allele homozygote frequency was 17% and the heterozygote frequency was 43%. The minor allele of rs2291075 was associated with lower %MMA (p = .0006) and higher %DMA (p = .0014), accounting for 7% of the variance for %MMA and 5% for %DMA. The frequency of rs2291075 minor allele homozygotes was 1% and of heterozygotes was 15%. Common variants in SLCO1B1 were associated with differences in arsenic metabolites in a preliminary candidate gene study. Replication of this finding in other populations and analyses with respect to disease outcomes are needed to determine whether this novel candidate gene is important for arsenic-associated disease risks.

SUBMITTER: Gribble MO

PROVIDER: S-EPMC3829571 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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SLCO1B1 variants and urine arsenic metabolites in the Strong Heart Family Study.

Gribble Matthew O MO Voruganti Venkata Saroja VS Cropp Cheryl D CD Francesconi Kevin A KA Goessler Walter W Umans Jason G JG Silbergeld Ellen K EK Laston Sandra L SL Haack Karin K Kao Wen Hong Linda WH Fallin Margaret Daniele MD Maccluer Jean W JW Cole Shelley A SA Navas-Acien Ana A

Toxicological sciences : an official journal of the Society of Toxicology 20130822 1

Arsenic species patterns in urine are associated with risk for cancer and cardiovascular diseases. The organic anion transporter coded by the gene SLCO1B1 may transport arsenic species, but its association with arsenic metabolites in human urine has not yet been studied. The objective of this study is to evaluate associations of urine arsenic metabolites with variants in the candidate gene SLCO1B1 in adults from the Strong Heart Family Study. We estimated associations between % arsenic species b ...[more]

PMID: 23970802

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Project description:BackgroundArsenic has been associated with hypertension, though it is unclear whether associations persist at the exposure concentrations (e.g. <100 μg/L) in drinking water occurring in parts of the Western United States.MethodsWe assessed associations between arsenic biomarkers and systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension in the Strong Heart Family Study, a family-based cohort of American Indians from the Northern plains, Southern plains, and Southwest. We included 1910 participants from three study centers with complete baseline visit data (2001-2003) in the cross-sectional analysis of all three outcomes, and 1453 participants in the prospective analysis of incident hypertension (follow-up 2006-2009). We used generalized estimating equations with exchangeable correlation structure conditional on family membership to estimate the association of arsenic exposure biomarker levels with SBP or DBP (linear regressions) or hypertension prevalence and incidence (Poisson regressions), adjusting for urine creatinine, urine arsenobetaine, and measured confounders.ResultsWe observed cross-sectional associations for a two-fold increase in inorganic and methylated urine arsenic species of 0.64 (95% CI: 0.07, 1.35) mm Hg for SBP, 0.49 (95% CI: 0.03, 1.02) mm Hg for DBP, and a prevalence ratio of 1.10 (95% CI: 1.01, 1.21) for hypertension in fully adjusted models. During follow-up, 14% of subjects developed hypertension. We observed non-monotonic relationships between quartiles of arsenic and incident hypertension. Effect estimates were null for incident hypertension with continuous exposure metrics. Stratification by study site revealed elevated associations in Arizona, the site with the highest arsenic levels, while results for Oklahoma and North and South Dakota were largely null. Blood pressure changes with increasing arsenic concentrations were larger for those with diabetes at baseline.ConclusionsOur results suggest a modest cross-sectional association of arsenic exposure biomarkers with blood pressure, and possible non-linear effects on incident hypertension.

Project description:The underlying pathology of arsenic-related cardiovascular disease (CVD) is unknown. Few studies have evaluated pathways through thrombosis and inflammation for arsenic-related CVD, especially at low-moderate arsenic exposure levels (<100 μg/L in drinking water). We evaluated the association of chronic low-moderate arsenic exposure, measured as the sum of inorganic and methylated arsenic species in urine (ΣAs), with plasma biomarkers of thrombosis and inflammation in American Indian adults (45-74 years) in the Strong Heart Study. We evaluated the cross-sectional and longitudinal associations between baseline ΣAs with fibrinogen at three visits (baseline, 1989-91; Visit 2, 1993-95, Visit 3, 1998-99) using mixed models and the associations between baseline ΣAs and Visit 2 plasminogen activator inhibitor-1 (PAI-1) and high sensitivity C-reactive protein (hsCRP) using linear regression. Median (interquartile range) concentrations of baseline ΣAs and fibrinogen, and Visit 2 hsCRP and PAI-1 were 8.4 (5.1, 14.3) μg/g creatinine, 346 (304, 393) mg/dL, 44 (30, 67) mg/L, and 3.8 (2.0, 7.0) ng/mL, respectively. Comparing the difference between the 75th and the 25th percentile of ΣAs (14.3 vs. 5.1 μg/g creatinine), ΣAs was positively associated with baseline fibrinogen among those with diabetes (adjusted geometric mean ratio (GMR): 1.05, 95% CI: 1.02, 1.07) not associated among those without diabetes (GMR: 1.01, 95% CI: 0.99, 1.02) (p-interaction for diabetes = 0.014), inversely associated with PAI-1 (GMR: 0.94, 95% CI: 0.90, 0.99), and not associated with hsCRP (GMR: 1.00, 95% CI: 0.93, 1.08). We found no evidence for an association between baseline ΣAs and annual change in fibrinogen over follow-up (p-interaction = 0.28 and 0.12 for diabetes and non-diabetes, respectively). Low-moderate arsenic exposure was positively associated with baseline fibrinogen in participants with diabetes and unexpectedly inversely associated with PAI-1. Further research should evaluate the role of prothrombotic factors in arsenic-related cardiovascular disease.

Project description:BackgroundInorganic arsenic exposure and inter-individual differences in its metabolism have been associated with cardiometabolic risk. A more efficient arsenic metabolism profile (lower MMA%, higher DMA%) has been associated with reduced risk for arsenic-related health outcomes; however, this profile has also been associated with increased risk for diabetes-related outcomes. The mechanism behind these contrasting associations is equivocal; we hypothesized one carbon metabolism (OCM) may play a role.MethodsWe evaluated the association between OCM-related variables (nutrient intake and genetic variants) and both arsenic metabolism biomarkers (iAs%, MMA% and DMA%) and diabetes-related outcomes (metabolic syndrome, diabetes, HOMA2-IR and waist circumference) in 935 participants free of prevalent diabetes and metabolic syndrome from the Strong Heart Family Study, a family-based prospective cohort comprised of American Indian tribal members aged 14+ years.ResultsOf the 935 participants free of both diabetes and metabolic syndrome at baseline, 279 (29.8%) developed metabolic syndrome over a median of 5.3 years of follow-up and of the 1458 participants free of diabetes at baseline, 167 (11.3%) developed diabetes over follow-up. OCM nutrients were not associated with arsenic metabolism, however, higher vitamin B6 was associated with diabetes-related outcomes (higher HOMA2-IR and increased risk for diabetes and metabolic syndrome). A polymorphism in an OCM-related gene, methionine synthase (MTR), was associated with both higher MMA% (β = 2.57, 95% CI: 0.22, 4.92) and lower HOMA2-IR (GMR = 0.79, 95% CI = 0.66, 0.93 per 5 years of follow-up). Adjustment for OCM variables did not affect previously reported associations between arsenic metabolism and diabetes-related outcomes; however, the association between the MTR variant and diabetes-related outcomes were attenuated after adjustment for arsenic metabolism.ConclusionsOur findings suggest MMA% may be a partial mediator in the association between OCM and diabetes-related outcomes. Additional mediation analyses with longer follow-up period are needed to confirm this finding. Further research is needed to determine whether excess B vitamin intake is associated with increased risk for diabetes-related outcomes.

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SLCO1B1 variants and urine arsenic metabolites in the Strong Heart Family Study.

Publications

SLCO1B1 variants and urine arsenic metabolites in the Strong Heart Family Study.

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