Abstract

Background:

By-products are formed when disinfectants react with organic matter in source water. The most common class of disinfection by-products, trihalomethanes (THMs), have been linked to bladder cancer. Several studies have shown exposure–response associations with THMs in drinking water and bladder cancer risk. Few epidemiologic studies have evaluated gene–environment interactions for total THMs (TTHMs) with known bladder cancer susceptibility variants.

Objectives:

In this study, we investigated the combined effect on bladder cancer risk contributed by TTHMs, bladder cancer susceptibility variants identified through genome-wide association studies, and variants in several candidate genes.

Methods:

We analyzed data from two large case–control studies—the New England Bladder Cancer Study ($n/n=989$ cases/1,162 controls), a population-based study, and the Spanish Bladder Cancer Study ($n/n=706$ cases/772 controls), a hospital-based study. Because of differences in exposure distributions and metrics, we estimated effects of THMs and genetic variants within each study separately using adjusted logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (CI) with and without interaction terms, and then combined the results using meta-analysis.

Results:

Of the 16 loci showing strong evidence of association with bladder cancer, rs907611 at 11p15.5 [leukocyte-specific protein 1 (LSP1 region)] showed the strongest associations in the highest exposure category in each study, with evidence of interaction in both studies and in meta-analysis. In the highest exposure category, we observed $\text{OR}=1.66$ (95% CI: 1.17, 2.34, $p\text{-trend}=0.005$) for those with the rs907611-GG genotype and $p\text{-interaction}=0.02$. No other genetic variants tested showed consistent evidence of interaction.

Discussion:

We found novel suggestive evidence for a multiplicative interaction between a putative bladder carcinogen, TTHMs, and genotypes of rs907611. Given the ubiquitous exposure to THMs, further work is needed to replicate and extend this finding and to understand potential molecular mechanisms. https://doi.org/10.1289/EHP9895

中文翻译：

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饮用水和膀胱癌中的消毒副产品：在两个病例对照研究中通过常见基因多态性评估风险修饰

摘要

背景：

消毒剂与水源中的有机物发生反应时会形成副产物。最常见的一类消毒副产品三卤甲烷 (THM) 与膀胱癌有关。几项研究表明，饮用水和膀胱癌风险中的 THM 与暴露反应相关。很少有流行病学研究评估了总 THM (TTHM) 与已知膀胱癌易感性变异的基因-环境相互作用。

目标：

在这项研究中，我们研究了 TTHM、通过全基因组关联研究确定的膀胱癌易感性变异以及几个候选基因的变异对膀胱癌风险的综合影响。

方法：

我们分析了来自两项大型病例对照研究的数据——新英格兰膀胱癌研究（$n/n=989$例/1,162 个对照）、一项基于人群的研究和西班牙膀胱癌研究（$n/n=706$例/772 个对照），一项基于医院的研究。由于暴露分布和指标的差异，我们使用调整后的逻辑回归模型分别估计了每项研究中 THM 和遗传变异的影响，以计算有和没有交互项的优势比 (OR) 和 95% 置信区间 (CI)，然后合并结果使用荟萃分析。

结果：

在显示与膀胱癌关联的有力证据的 16 个位点中，11p15.5 [白细胞特异性蛋白 1（LSP1区域）] 的 rs907611 在每项研究中显示出最高暴露类别中最强的关联，在这两项研究和在荟萃分析中。在最高曝光类别中，我们观察到$\text{或者}=1.66$(95% CI: 1.17, 2.34,$p\text{-趋势}=0.005$) 对于那些具有 rs907611-GG 基因型和$p\text{-相互作用}=0.02$. 没有其他测试的遗传变异显示出一致的相互作用证据。

讨论：

我们发现了推定的膀胱致癌物、TTHMs 和 rs907611 基因型之间的乘法相互作用的新的暗示性证据。鉴于 THM 无处不在，需要进一步的工作来复制和扩展这一发现并了解潜在的分子机制。https://doi.org/10.1289/EHP9895