Serum homocysteine, arsenic methylation, and arsenic-induced skin lesion incidence in Bangladesh: A one-carbon metabolism candidate gene study

Megan M. Niedzwiecki, Xinhua Liu, Huiping Zhu, Megan N. Hall, Vesna Slavkovich, Vesna Ilievski, Diane Levy, Abu B. Siddique, Muhammad G. Kibriya, Faruque Parvez, Tariqul Islam, Alauddin Ahmed, Ana Navas-Acien, Joseph H. Graziano, Richard H. Finnell, Habibul Ahsan, Mary V. Gamble

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)133-142
Number of pages10
JournalEnvironment international
Volume113
DOIs
StatePublished - Apr 2018

Keywords

  • Arsenic
  • Arsenic metabolism
  • Gene-environment interaction
  • Homocysteine
  • One-carbon metabolism
  • Skin lesions

ASJC Scopus subject areas

  • Environmental Science(all)

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