Though bladder cancer has been the subject of many well-powered genome-wide association studies, the mechanisms involving bladder-cancer-associated single nucleotide polymorphisms (SNPs) remain largely unknown. This study focuses on rs798766, rs401681, rs2294008, and rs8102137, which have been associated with bladder cancer and are also cis-acting methylation quantitative loci (mQTL). Among 412 bladder cancer cases and 424 controls from the Women’s Health Initiative (WHI), we assessed whether the effects of these SNPs on bladder cancer are mediated through proximal DNA methylation changes in pre-diagnostic blood at mQTL-associated CpG sites, which we refer to as natural indirect effects (NIEs). We used a multiple-mediator mediation model for each of the four mQTL adjusted for matching variables and potential confounders, including race/ethnicity, smoking status, and pack-years of smoking. While not statistically significant, our results suggest that substantial proportions of the modest effects of rs401681 (ORNIE = 1.05, 95% confidence interval (CI) = 0.89 to 1.25; NIE percent = 98.5%) and rs2294008 (ORNIE = 1.10, 95% CI = 0.90 to 1.33; NIE percent = 77.6%) on bladder cancer risk are mediated through differential DNA methylation at nearby mQTL-associated CpG sites. The suggestive results indicate that rs2294008 may affect bladder cancer risk through a set of genes in the lymphocyte antigen 6 family, which involves genes that bind to and modulate nicotinic acetylcholine receptors. There was no suggestive evidence supporting mediation for rs8102137 and rs798766. Though larger studies are necessary, the methylation changes associated with rs401681 and rs2294008 at mQTL-associated CpG sites may be relevant for bladder carcinogenesis, and this study demonstrates how multi-omic data can be integrated to help understand the downstream effects of genetics variants.

中文翻译：

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DNA甲基化差异介导的单核苷酸多态性与膀胱癌风险之间的已知关联

尽管膀胱癌一直是许多功能强大的全基因组关联研究的主题，但与膀胱癌相关的单核苷酸多态性（SNPs）涉及的机制仍然未知。这项研究的重点是与膀胱癌相关的rs798766，rs401681，rs2294008和rs8102137，它们也是顺式作用甲基化定量基因座（mQTL）。在来自妇女健康倡议组织（WHI）的412例膀胱癌病例和424例对照中，我们评估了这些SNP对膀胱癌的影响是否通过mQTL相关CpG位点的预诊断血中的近端DNA甲基化变化介导。作为自然间接效应（NIE）。对于四个mQTL中的每一个，我们都使用了多媒介中介模型，该模型针对匹配变量和潜在的混杂因素（包括种族/民族，吸烟状况和吸烟年限。尽管没有统计学显着性，但我们的结果表明rs401681（ORNIE = 1.05，95％置信区间（CI）= 0.89至1.25； NIE％= 98.5％）和rs2294008（ORNIE = 1.10，95％CI = 0.90至1.33； NIE百分比= 77.6％）是通过附近mQTL相关CpG位点的差异DNA甲基化介导的。提示性结果表明，rs2294008可能通过淋巴细胞抗原6家族中的一组基因影响膀胱癌的风险，该基因涉及与烟碱样乙酰胆碱受体结合并对其进行调节的基因。没有暗示性证据支持对rs8102137和rs798766进行调解。尽管有必要进行更大的研究，