title: Arsenic metabolism, genetic susceptibility, and risk of premalignant skin lesions in Bangladesh.
abstract: We conducted a case-control study to investigate interindividual variability in susceptibility to health effects of inorganic arsenic due to arsenic metabolism efficiency, genetic factors, and their interaction. A total of 594 cases of arsenic-induced skin lesions and 1,041 controls was selected from baseline participants in a large prospective cohort study in Bangladesh. Adjusted odds ratios (OR) for skin lesions were estimated in relation to the polymorphisms in the glutathione S-transferase omega1 and methylenetetrahydrofolate reductase genes, the percentage of monomethylarsonous acid (%MMA) and dimethylarsinic acid (%DMA) in urine, and the ratios of MMA to inorganic arsenic and DMA to MMA. Water arsenic concentration was positively associated with %MMA and inversely associated with %DMA. The dose-response relationship of risk of skin lesion with %MMA was more apparent than those with other methylation indices; the ORs for skin lesions in relation to increasing %MMA quartiles were 1.00 (reference), 1.33 [95% confidence interval (95% CI), 0.92-1.93], 1.68 (95% CI, 1.17-2.42), and 1.57 (95% CI, 1.10-2.26; P for trend = 0.01). The ORs for skin lesions in relation to the methylenetetrahydrofolate reductase 677TT/1298AA and 677CT/1298AA diplotypes (compared with 677CC/1298CC diplotype) were 1.66 (95% CI, 1.00-2.77) and 1.77 (95% CI, 0.61-5.14), respectively. The OR for skin lesions in relation to the glutathione S-transferase omega1 diplotype containing all at-risk alleles was 3.91 (95% CI, 1.03-14.79). Analysis of joint effects of genotypes/diplotypes with water arsenic concentration and urinary %MMA suggests additivity of these factors. The findings suggest that arsenic metabolism, particularly the conversion of MMA to DMA, may be saturable and that differences in urinary arsenic metabolites, genetic factors related to arsenic metabolism, and their joint distributions modulate arsenic toxicity.
authors.affiliation: Departments of Epidemiology, Columbia University, USA. habib@uchicago.edu
authors.forename: Habibul
authors.initials: H
authors.lastname: Ahsan
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Muhammad G
authors.initials: MG
authors.lastname: Kibriya
authors.forename: Vesna
authors.initials: V
authors.lastname: Slavkovich
authors.forename: Faruque
authors.initials: F
authors.lastname: Parvez
authors.forename: Farzana
authors.initials: F
authors.lastname: Jasmine
authors.forename: Mary V
authors.initials: MV
authors.lastname: Gamble
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Graziano
mesh_terms: D001151:Arsenic / Q000378:metabolism* / Q000633:toxicity; D020261:Arsenic Poisoning / Q000235:genetics; D001459:Bangladesh; D002101:Cacodylic Acid / Q000652:urine; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008297:Male; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics; D009942:Organometallic Compounds / Q000652:urine; D020641:Polymorphism, Single Nucleotide; D011230:Precancerous Conditions / Q000235:genetics*; D012871:Skin Diseases / Q000139:chemically induced* / Q000235:genetics*; D014874:Water Pollutants, Chemical / Q000009:adverse effects; D014877:Water Pollution, Chemical / Q000009:adverse effects
chemical_list: D009942:Organometallic Compounds; D014874:Water Pollutants, Chemical; C406082:monomethylarsonous acid; D002101:Cacodylic Acid; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D005982:Glutathione Transferase; D001151:Arsenic