TY - JOUR
T1 - Serum homocysteine, arsenic methylation, and arsenic-induced skin lesion incidence in Bangladesh
T2 - A one-carbon metabolism candidate gene study
AU - Niedzwiecki, Megan M.
AU - Liu, Xinhua
AU - Zhu, Huiping
AU - Hall, Megan N.
AU - Slavkovich, Vesna
AU - Ilievski, Vesna
AU - Levy, Diane
AU - Siddique, Abu B.
AU - Kibriya, Muhammad G.
AU - Parvez, Faruque
AU - Islam, Tariqul
AU - Ahmed, Alauddin
AU - Navas-Acien, Ana
AU - Graziano, Joseph H.
AU - Finnell, Richard H.
AU - Ahsan, Habibul
AU - Gamble, Mary V.
N1 - Funding Information:
This work was supported by the National Institutes of Health [grants R01 CA133595 , R01 ES017875 , P42 ES10349 , P30 ES009089 , and T32 CA009529-24 ]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Environmental Health Sciences, the National Cancer Institute, or the National Institutes of Health.
Funding Information:
This work was supported by the National Institutes of Health [grants R01 CA133595, R01 ES017875, P42 ES10349, P30 ES009089, and T32 CA009529-24]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Environmental Health Sciences, the National Cancer Institute, or the National Institutes of Health.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/4
Y1 - 2018/4
N2 - 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.
AB - 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.
KW - Arsenic
KW - Arsenic metabolism
KW - Gene-environment interaction
KW - Homocysteine
KW - One-carbon metabolism
KW - Skin lesions
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U2 - 10.1016/j.envint.2018.01.015
DO - 10.1016/j.envint.2018.01.015
M3 - Article
C2 - 29421402
AN - SCOPUS:85041672134
SN - 0160-4120
VL - 113
SP - 133
EP - 142
JO - Environment international
JF - Environment international
ER -