TY - JOUR
T1 - Arsenic metabolism efficiency has a causal role in arsenic toxicity
T2 - Mendelian randomization and gene-environment interaction
AU - Pierce, Brandon L.
AU - Tong, Lin
AU - Argos, Maria
AU - Gao, Jianjun
AU - Jasmine, Farzana
AU - Roy, Shantanu
AU - Paul-Brutus, Rachelle
AU - Rahaman, Ronald
AU - Rakibuz-Zaman, Muhammad
AU - Parvez, Faruque
AU - Ahmed, Alauddin
AU - Quasem, Iftekhar
AU - Hore, Samar K.
AU - Alam, Shafiul
AU - Islam, Tariqul
AU - Harjes, Judith
AU - Sarwar, Golam
AU - Slavkovich, Vesna
AU - Gamble, Mary V.
AU - Chen, Yu
AU - Yunus, Mohammad
AU - Rahman, Mahfuzar
AU - Baron, John A.
AU - Graziano, Joseph H.
AU - Ahsan, Habibul
N1 - Funding Information:
This work was supported by National Institutes of Health (NIH) grants R01ES020506, P42ES010349, R01CA102484, R01CA107431 and P30CA014599.
PY - 2013/12
Y1 - 2013/12
N2 - Background Arsenic exposure through drinking water is a serious global health issue. Observational studies suggest that individuals who metabolize arsenic efficiently are at lower risk for toxicities such as arsenical skin lesions. Using two single nucleotide polymorphisms (SNPs) in the 10q24.32 region (near AS3MT) that show independent associations with metabolism efficiency, Mendelian randomization can be used to assess whether the association between metabolism efficiency and skin lesions is likely to be causal.Methods Using data on 2060 arsenic-exposed Bangladeshi individuals, we estimated associations for two 10q24.32 SNPs with relative concentrations of three urinary arsenic species (representing metabolism efficiency): inorganic arsenic (iAs), monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). SNP-based predictions of iAs%, MMA% and DMA% were tested for association with skin lesion status among 2483 cases and 2857 controls.Results Causal odds ratios for skin lesions were 0.90 (95% confidence interval [CI]: 0.87, 0.95), 1.19 (CI: 1.10, 1.28) and 1.23 (CI: 1.12, 1.36) for a one standard deviation increase in DMA%, MMA% and iAs%, respectively. We demonstrated genotype-arsenic interaction, with metabolism-related variants showing stronger associations with skin lesion risk among individuals with high arsenic exposure (synergy index: 1.37; CI: 1.11, 1.62).Conclusions We provide strong evidence for a causal relationship between arsenic metabolism efficiency and skin lesion risk. Mendelian randomization can be used to assess the causal role of arsenic exposure and metabolism in a wide array of health conditions. Developing interventions that increase arsenic metabolism efficiency are likely to reduce the impact of arsenic exposure on health. Published by Oxford University Press on behalf of the International Epidemiological Association
AB - Background Arsenic exposure through drinking water is a serious global health issue. Observational studies suggest that individuals who metabolize arsenic efficiently are at lower risk for toxicities such as arsenical skin lesions. Using two single nucleotide polymorphisms (SNPs) in the 10q24.32 region (near AS3MT) that show independent associations with metabolism efficiency, Mendelian randomization can be used to assess whether the association between metabolism efficiency and skin lesions is likely to be causal.Methods Using data on 2060 arsenic-exposed Bangladeshi individuals, we estimated associations for two 10q24.32 SNPs with relative concentrations of three urinary arsenic species (representing metabolism efficiency): inorganic arsenic (iAs), monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). SNP-based predictions of iAs%, MMA% and DMA% were tested for association with skin lesion status among 2483 cases and 2857 controls.Results Causal odds ratios for skin lesions were 0.90 (95% confidence interval [CI]: 0.87, 0.95), 1.19 (CI: 1.10, 1.28) and 1.23 (CI: 1.12, 1.36) for a one standard deviation increase in DMA%, MMA% and iAs%, respectively. We demonstrated genotype-arsenic interaction, with metabolism-related variants showing stronger associations with skin lesion risk among individuals with high arsenic exposure (synergy index: 1.37; CI: 1.11, 1.62).Conclusions We provide strong evidence for a causal relationship between arsenic metabolism efficiency and skin lesion risk. Mendelian randomization can be used to assess the causal role of arsenic exposure and metabolism in a wide array of health conditions. Developing interventions that increase arsenic metabolism efficiency are likely to reduce the impact of arsenic exposure on health. Published by Oxford University Press on behalf of the International Epidemiological Association
KW - AS3MT
KW - Arsenic
KW - Arsenic metabolism
KW - Gene-environment interaction
KW - Mendelian randomization
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U2 - 10.1093/ije/dyt182
DO - 10.1093/ije/dyt182
M3 - Article
C2 - 24536095
AN - SCOPUS:84892468257
SN - 0300-5771
VL - 42
SP - 1862
EP - 1872
JO - International Journal of Epidemiology
JF - International Journal of Epidemiology
IS - 6
M1 - dyt182
ER -