Arsenic metabolism efficiency has a causal role in arsenic toxicity: Mendelian randomization and gene-environment interaction

Brandon L. Pierce, Lin Tong, Maria Argos, Jianjun Gao, Farzana Jasmine, Shantanu Roy, Rachelle Paul-Brutus, Ronald Rahaman, Muhammad Rakibuz-Zaman, Faruque Parvez, Alauddin Ahmed, Iftekhar Quasem, Samar K. Hore, Shafiul Alam, Tariqul Islam, Judith Harjes, Golam Sarwar, Vesna Slavkovich, Mary V. Gamble, Yu ChenMohammad Yunus, Mahfuzar Rahman, John A. Baron, Joseph H. Graziano, Habibul Ahsan

Research output: Contribution to journalArticlepeer-review


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

Original languageEnglish (US)
Article numberdyt182
Pages (from-to)1862-1872
Number of pages11
JournalInternational Journal of Epidemiology
Issue number6
StatePublished - Dec 2013


  • AS3MT
  • Arsenic
  • Arsenic metabolism
  • Gene-environment interaction
  • Mendelian randomization

ASJC Scopus subject areas

  • Epidemiology


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