Genome-Wide Association Study Identifies Chromosome 10q24.32 Variants Associated with Arsenic Metabolism and Toxicity Phenotypes in Bangladesh

Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10−8) for percentages of both monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) near the AS3MT gene (arsenite methyltransferase; 10q24.32), with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity) and 1,794 controls, we show that one of these five variants (rs9527) is also associated with skin lesion risk (P = 0.0005). Using a subset of individuals with prospectively measured arsenic (n = 769), we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P = 0.01). Expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P = 10−12) and neighboring gene C10orf32 (P = 10−44), which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical skin lesion risk. The observed patterns of associations suggest that MMA% and DMA% have distinct genetic determinants and support the hypothesis that DMA is the less toxic of these two methylated arsenic species. These results have potential translational implications for the prevention and treatment of arsenic-associated toxicities worldwide

Arsenic exposure, telomere length, and expression of telomere-related genes among Bangladeshi individuals

Inorganic arsenic is a carcinogen whose mode of action may involve telomere dysfunction. Recent epidemiological studies suggest that chronic arsenic exposure is associated with longer telomeres and altered expression of telomere-related genes in peripheral blood. In this study, we evaluated the association of urinary arsenic concentration with expression of telomere-related genes and telomere length in Bangladeshi individuals with a wide range of arsenic exposure through naturally contaminated drinking water

Genome-Wide Association Study Identifies Chromosome 10q24.32 Variants Associated with Arsenic Metabolism and Toxicity Phenotypes in Bangladesh

Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10−8) for percentages of both monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) near the AS3MT gene (arsenite methyltransferase; 10q24.32), with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity) and 1,794 controls, we show that one of these five variants (rs9527) is also associated with skin lesion risk (P = 0.0005). Using a subset of individuals with prospectively measured arsenic (n = 769), we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P = 0.01). Expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P = 10−12) and neighboring gene C10orf32 (P = 10−44), which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical skin lesion risk. The observed patterns of associations suggest that MMA% and DMA% have distinct genetic determinants and support the hypothesis that DMA is the less toxic of these two methylated arsenic species. These results have potential translational implications for the prevention and treatment of arsenic-associated toxicities worldwide

Multivariate associations between arsenic metabolites and genotyped SNPs in the 10q24.32 region showing the strongest univariate associations with DMA% and MMA% (n = 1,313).

<p>Regression models including all five SNPs in a single model, adjusting for age, sex, and water arsenic. All regressions were mixed models carried out using EMMAX.</p>a<p>MA, minor allele.</p>b<p>MAF, minor allele frequency.</p

Multiple variants in the 10q24.32 region show independent associations with DMA% (n = 1,313).

<p>P-values were generated using mixed models adjusted for age, sex, and water arsenic concentration. The strongest associated SNP is labeled in each panel. Panel A shows the overall association results. Panel B shows P-values from models that are adjusted for rs9527. Panel C shows P-values from models adjusted for both rs9527 and rs11191527.</p

Association between the 10q24.32 genotyped variants and arsenical skin lesion risk and SNP-arsenic interaction estimates.

a<p>MA, minor allele.</p>b<p>Each Logistic Regression model includes one SNP, adjusting for age and sex.</p>c<p>The ROADTRIPS case-control test does not allow multivariate modeling (i.e., no adjustments), but accounts for cryptic relatedness.</p>d<p>Interaction P-values are from mixed linear models that account for relatedness among subjects. Interactions are on the additive scale and are calculated using data on 69 cases and incident 700 controls.</p

Multiple variants in the 10q24.32 region show independent associations with MMA% (n = 1,313).

<p>P-values were generated using mixed models adjusted for age, sex, and water arsenic concentration. The strongest associated SNP is labeled in each panel. Panel A shows the overall association results. Panel B shows P-values from models that are adjusted for rs4919694. Panel C shows P-values from models adjusted for both rs4919694 and rs4290163.</p

Arsenic exposure, telomere length, and expression of telomere-related genes among Bangladeshi individuals

BACKGROUND: Inorganic arsenic is a carcinogen whose mode of action may involve telomere dysfunction. Recent epidemiological studies suggest that chronic arsenic exposure is associated with longer telomeres and altered expression of telomere-related genes in peripheral blood. In this study, we evaluated the association of urinary arsenic concentration with expression of telomere-related genes and telomere length in Bangladeshi individuals with a wide range of arsenic exposure through naturally contaminated drinking water. METHODS: We used linear regression models to estimate associations between urinary arsenic and array-based expression measures for 69 telomere related genes using mononuclear cell RNA samples from 1,799 individuals. Association between arsenic exposure and a qPCR-based telomere length was assessed among 167 individuals. RESULTS: Urinary arsenic was possitively associated with expression of WRN, and negatively associated with TERF2, DKC1, TERF2IP and OBFC1 (all P < 0.00035, Bonferroni correction threshold). We detected interaction between urinary arsenic and arsenic metabolism efficiency in relation to expression of WRN (P for interaction = 0.00008). In addition, we observed that very high arsenic exposure was associated with longer telomeres compared to very low exposure (P=0.02). DISCUSSION: Our findings suggest that arsenic’s carcinogenic mode of action may involve alteration of telomere maintenance and/or telomere damage. This study extends our knowledge regarding the effect of arsenic on telomere length and expression of telomere-related genes