title: Arsenic metabolism efficiency has a causal role in arsenic toxicity: Mendelian randomization and gene-environment interaction.
abstract: 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.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.
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Pierce
authors.forename: Lin
authors.initials: L
authors.lastname: Tong
authors.forename: Maria
authors.initials: M
authors.lastname: Argos
authors.forename: Jianjun
authors.initials: J
authors.lastname: Gao
authors.forename: Jasmine
authors.initials: J
authors.lastname: Farzana
authors.forename: Shantanu
authors.initials: S
authors.lastname: Roy
authors.forename: Rachelle
authors.initials: R
authors.lastname: Paul-Brutus
authors.forename: Ronald
authors.initials: R
authors.lastname: Rahaman
authors.forename: Muhammad
authors.initials: M
authors.lastname: Rakibuz-Zaman
authors.forename: Faruque
authors.initials: F
authors.lastname: Parvez
authors.forename: Alauddin
authors.initials: A
authors.lastname: Ahmed
authors.forename: Iftekhar
authors.initials: I
authors.lastname: Quasem
authors.forename: Samar K
authors.initials: SK
authors.lastname: Hore
authors.forename: Shafiul
authors.initials: S
authors.lastname: Alam
authors.forename: Tariqul
authors.initials: T
authors.lastname: Islam
authors.forename: Judith
authors.initials: J
authors.lastname: Harjes
authors.forename: Golam
authors.initials: G
authors.lastname: Sarwar
authors.forename: Vesna
authors.initials: V
authors.lastname: Slavkovich
authors.forename: Mary V
authors.initials: MV
authors.lastname: Gamble
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Mohammad
authors.initials: M
authors.lastname: Yunus
authors.forename: Mahfuzar
authors.initials: M
authors.lastname: Rahman
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Graziano
authors.forename: Habibul
authors.initials: H
authors.lastname: Ahsan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D020261:Arsenic Poisoning / Q000150:complications / Q000453:epidemiology* / Q000235:genetics; D001152:Arsenicals / Q000378:metabolism* / Q000652:urine; D001459:Bangladesh / Q000453:epidemiology; D002101:Cacodylic Acid / Q000652:urine; D015984:Causality; D015331:Cohort Studies; D004781:Environmental Exposure / Q000706:statistics & numerical data*; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008780:Methyltransferases / Q000235:genetics*; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012871:Skin Diseases / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics; D055815:Young Adult
chemical_list: D001152:Arsenicals; D002101:Cacodylic Acid; D008780:Methyltransferases; C505756:AS3MT protein, human; C020300:monomethylarsonic acid