Mediation by differential DNA methylation of known associations between single nucleotide polymorphisms and bladder cancer risk.

4区医学 Q4 Medicine

BMC Medical Genetics Pub Date : 2020-11-19 DOI:10.1186/s12881-020-01172-1

Kristina M Jordahl, Amanda I Phipps, Timothy W Randolph, Lesley F Tinker, Rami Nassir, Lifang Hou, Garnet L Anderson, Karl T Kelsey, Emily White, Parveen Bhatti

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引用次数: 3

Abstract

Background: 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).

Methods: 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.

Results: While not statistically significant, our results suggest that substantial proportions of the modest effects of rs401681 (OR^NIE = 1.05, 95% confidence interval (CI) = 0.89 to 1.25; NIE percent = 98.5%) and rs2294008 (OR^NIE = 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.

Conclusions: 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.

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单核苷酸多态性与膀胱癌风险之间已知关联的差异DNA甲基化介导。

背景:尽管膀胱癌已成为许多全基因组关联研究的主题，但膀胱癌相关单核苷酸多态性(SNPs)的机制在很大程度上仍然未知。本研究重点关注与膀胱癌相关的rs798766、rs401681、rs2294008和rs8102137，它们也是顺式作用的甲基化定量位点(mQTL)。方法:在来自妇女健康倡议(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诊断前血液中mqtl相关CpG位点的近端DNA甲基化变化介导，我们称之为自然间接效应(NIEs)。我们对四个mQTL中的每一个使用了多中介中介模型，对匹配变量和潜在混杂因素进行了调整，包括种族/民族、吸烟状况和吸烟包年。结果:虽然没有统计学意义，但我们的结果表明，rs401681的适度效应(ORNIE = 1.05, 95%可信区间(CI) = 0.89 ~ 1.25;NIE百分比= 98.5%)和rs2294008 (ORNIE = 1.10, 95% CI = 0.90 ~ 1.33;(百分比= 77.6%)通过附近mqtl相关CpG位点的差异DNA甲基化介导膀胱癌风险。提示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风险，这些基因涉及结合和调节烟碱乙酰胆碱受体的基因。没有证据表明rs8102137和rs798766具有中介作用。结论:虽然需要更大规模的研究，但与rs401681和rs2294008相关的mqtl相关CpG位点的甲基化变化可能与膀胱癌发生有关，本研究表明如何整合多组学数据来帮助理解遗传变异的下游影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

BMC Medical Genetics 医学-遗传学

自引率

0.00%

发文量

审稿时长

12 months

期刊介绍： BMC Medical Genetics is an open access journal publishing original peer-reviewed research articles in the effects of genetic variation in individuals, families and among populations in relation to human health and disease. Note: BMC Medical Genetics is now closed. This journal has merged with BMC Medical Genomics, a broad-scope, open access community journal for all medical genetics and genomics research.