Serum homocysteine, arsenic methylation, and arsenic-induced skin lesion incidence in Bangladesh: A one-carbon metabolism candidate gene study.
BACKGROUND
Inorganic arsenic (As) is methylated via one carbon metabolism (OCM) to mono- and dimethylated arsenicals (MMA and DMA), facilitating urinary excretion. Hyperhomocysteinemia (HHcys), a marker of impaired OCM, is a risk factor for As-induced skin lesions, but the influences of single nucleotide polymorphisms (SNPs) in OCM genes on Hcys, As metabolism and skin lesion risk is unclear.


OBJECTIVES
To (i) explore genetic sources of Hcys and the causal role of HHcys in As-induced skin lesion development using OCM genetic proxies for HHcys and (ii) identify OCM SNPs associated with urinary As metabolite proportions and/or skin lesion incidence.


METHODS
We conducted a case-control study nested in the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh which 876 incident skin lesion cases were matched to controls on sex, age, and follow-up time. We measured serum Hcys, urinary As metabolites, and 26 SNPs in 13 OCM genes.


RESULTS
Serum Hcys and urinary %DMA were independently associated with increased and decreased odds of skin lesions, respectively. The T allele of MTHFR 677 C ➔ T (rs1801133) was associated with HHcys, higher %MMA, and lower %DMA, but not with skin lesions. Interactions between SNPs and water As on skin lesion risk were suggestive for three variants: the G allele of MTRR rs1801394 and T allele of FOLR1 rs1540087 were associated with lower odds of skin lesions with lower As (≤50 μg/L), and the T allele of TYMS rs1001761 was associated with higher odds of skin lesions with higher As.


CONCLUSIONS
While HHcys and decreased %DMA were associated with increased risk for skin lesions, and MTHFR 677 C ➔ T was a strong predictor of HHcys, MTHFR 677 C ➔ T was not associated with skin lesion risk. Future studies should explore (i) non-OCM and non-genetic determinants of Hcys and (ii) if genetic findings are replicated in other As-exposed populations, mechanisms by which OCM SNPs may influence the dose-dependent effects of As on skin lesion risk.
['Niedzwiecki|Megan M|MM|', 'Liu|Xinhua|X|', 'Zhu|Huiping|H|', 'Hall|Megan N|MN|', 'Slavkovich|Vesna|V|', 'Ilievski|Vesna|V|', 'Levy|Diane|D|', 'Siddique|Abu B|AB|', 'Kibriya|Muhammad G|MG|', 'Parvez|Faruque|F|', 'Islam|Tariqul|T|', 'Ahmed|Alauddin|A|', 'Navas-Acien|Ana|A|', 'Graziano|Joseph H|JH|', 'Finnell|Richard H|RH|', 'Ahsan|Habibul|H|', 'Gamble|Mary V|MV|']
D001151:Arsenic D001152:Arsenicals D001459:Bangladesh D016022:Case-Control Studies D020022:Genetic Predisposition to Disease D006710:Homocysteine D006801:Humans D008745:Methylation D020641:Polymorphism, Single Nucleotide D012871:Skin Diseases
Homocysteine Arsenic Skin lesions One-carbon metabolism Arsenic metabolism Gene-environment interaction