Lin Y.-C.Chen W.-J.CHAO-YUAN HUANGShiue H.-S.Su C.-T.Ao P.-L.YEONG-SHIAU PUHsueh Y.-M.2021-02-022021-02-0220181096-6080https://www.scopus.com/inward/record.uri?eid=2-s2.0-85050800445&doi=10.1093%2ftoxsci%2fkfy087&partnerID=40&md5=cfa5c514e515f129295e33eeb41be56bhttps://scholars.lib.ntu.edu.tw/handle/123456789/544310The mechanisms underlying how arsenicmethylation capacity affects bladder cancer (BC) are still unclear. The objective of this study was to explore the effects of polymorphisms of arsenic (+3 oxidation state) methyltransferase (AS3MT) on BC risk. We conducted a hospital-based study and enrolled 216 BC and 648 healthy controls from2007 to 2011. Urinary arsenic profiles weremeasured using high-performance liquid chromatography-hydride generation-atomic absorption spectrometry. The gene polymorphisms of AS3MT were identified using the SequenomMassARRAY platform with iPLEX Gold chemistry. Inefficient arsenicmethylation capacity (highmonomethylarsonic acid percentage [MMA%] and low dimethylarsinic acid percentage [DMA%]) was associated with increased risk of BC in a dose-response relationship. AS3MT rs11191438 (C > G) G/G genotype, AS3MT rs10748835 (A > G) G/G genotype, and AS3MT rs1046778 (C > T) T/T genotype were found to be related to BC risk, where the odds ratio (OR) (95% CI) was 0.50 (0.31-0.82), 0.49 (0.30-0.79), and 0.54 (0.36-0.80), respectively. The combination of AS3MT haplotype 2 (AS3MT rs11191453, rs11191454, rs10748835, and rs1046778)'s high-risk haplotype (C-G-A-C, T-A-A-C, and T-G-G-T) was significantly associated with increased risk of BC. Among controls, only 3 of the 9 candidate genotypes evaluated, rs1119438 C/C, rs10748835 A/A and rs1046778 C/C, were associated with significantly higherMMA% compared with the other genotypes. No other genotypes or haplotypes were related to arsenicmethylation capacity. HighMMA%, low DMA% and AS3MT rs1046778 C/C + C/T genotype predicted a significantly higher risk of BC according to stepwisemultiple logistic regression analyses. AS3MT gene polymorphisms and arsenicmethylation capacity appeared to affect BC risk independently. ? The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.[SDGs]SDG3[SDGs]SDG6arsenic derivative; cacodylic acid; creatinine; methanearsonic acid; methyltransferase; arsenic; AS3MT protein, human; methyltransferase; adult; Article; atomic absorption spectrometry; bladder cancer; cancer risk; cigarette smoking; controlled study; creatinine urine level; female; genetic association; genetic risk; haplotype; high performance liquid chromatography; human; major clinical study; male; middle aged; oxidation; single nucleotide polymorphism; bladder tumor; case control study; enzymology; genetic predisposition; genetics; metabolism; methylation; risk; social aspects and related phenomena; statistical model; urine; Arsenic; Case-Control Studies; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Logistic Models; Male; Methylation; Methyltransferases; Middle Aged; Polymorphism, Single Nucleotide; Risk; Sociological Factors; Urinary Bladder Neoplasmsjournal article10.1093/toxsci/kfy087296690442-s2.0-85050800445