Pomares-Millan Hugo, Koutros Stella, Baris Dalsu, Schwenn Molly, Johnson Alison, Rothman Nathaniel, Silverman Debra T, Leach Steven D, Karagas Margaret R, Passarelli Michael N
Department of Epidemiology, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Hanover, Lebanon, NH, United States.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, MD, United States.
JNCI Cancer Spectr. 2025 Jul 1;9(4). doi: 10.1093/jncics/pkaf064.
Exposure to arsenic in drinking water may interact with common genetic variants in urinary bladder cancer risk.
We conducted a gene-environment interaction analysis among 1091 bladder cancer cases and 928 controls from the New England Bladder Cancer Study. Genetic variants tested as effect modifiers included those associated with bladder cancer and arsenic metabolism. Interactions with disease-specific polygenic scores and a genome-wide gene-environment interaction analysis were also conducted. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated with average arsenic concentration (µg/L), average daily arsenic (µg/day), and cumulative arsenic (mg) in water as exposures.
Multiplicative interactions for bladder cancer risk were identified for cumulative arsenic and rs1046428 of GSTZ1 on 14q23 (TT and TC genotype: ORT3vsT1 = 1.44, 95% CI = 1.05 to 1.98; Pinteraction = .01) and for average daily arsenic and rs1801133 (C677T) and rs1801131 (A1298C) of MTHFR on 1p36 (TT and TC genotypes: ORT3vsT1 = 1.53, 95% CI = 1.06 to 2.23; Pinteraction = .02; CC and CA genotype: ORT3vsT1 = 1.63, 95% CI = 1.16 to 2.29; Pinteraction =.01, respectively). A global interaction between arsenic exposure and polygenic scores was also observed (ORT3vsT1 = 1.80, 95% CI = 1.26 to 2.56; Pinteraction =. 01). Genome-wide gene-environment interaction analyses suggested interactions with 5 loci with a Pinteraction of no more than 5e-6.
Genetic variants that function in arsenic metabolism involving folate and oxidative stress pathways and a global summary of genetic susceptibility to bladder cancer may modify the association between elevated arsenic exposure from drinking water and bladder cancer.
饮用水中砷暴露可能与膀胱癌风险的常见基因变异相互作用。
我们对新英格兰膀胱癌研究中的1091例膀胱癌病例和928例对照进行了基因-环境相互作用分析。作为效应修饰因子进行检测的基因变异包括与膀胱癌和砷代谢相关的变异。还进行了与疾病特异性多基因评分的相互作用以及全基因组基因-环境相互作用分析。以水中平均砷浓度（μg/L）、平均每日砷摄入量（μg/天）和累积砷量（mg）作为暴露因素，估计比值比（OR）及其95%置信区间（CI）。
确定了累积砷与14q23上GSTZ1的rs1046428在膀胱癌风险方面的相乘相互作用（TT和TC基因型：ORT3vsT1 = 1.44，95%CI = 1.05至1.98；P相互作用 = 0.01），以及平均每日砷与1p36上MTHFR的rs1801133（C677T）和rs1801131（A1298C）在膀胱癌风险方面的相乘相互作用（TT和TC基因型：ORT3vsT1 = 1.53，95%CI = 1.06至2.23；P相互作用 = 0.02；CC和CA基因型：ORT3vsT1 = 1.63，95%CI = 1.16至2.29；P相互作用分别为0.01）。还观察到砷暴露与多基因评分之间的总体相互作用（ORT3vsT1 = 1.80，95%CI = 1.26至2.56；P相互作用 = 0.01）。全基因组基因-环境相互作用分析表明与5个位点存在相互作用，P相互作用不超过5e-6。
在涉及叶酸和氧化应激途径的砷代谢中起作用的基因变异以及膀胱癌遗传易感性的总体概况可能会改变饮用水中砷暴露增加与膀胱癌之间的关联。
