Pathway-Specific Polygenic Risk Scores Identify Obstructive Sleep Apnea-Related Pathways Differentially Moderating Genetic Susceptibility to Coronary Artery Disease.
Pathway-Specific Polygenic Risk Scores Identify Obstructive Sleep Apnea-Related Pathways Differentially Moderating Genetic Susceptibility to Coronary Artery Disease.
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DOI：
10.1161/circgen.121.003535
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发表时间：
2022-10
影响因子：
7.4
通讯作者：
Redline, Susan
中科院分区：
文献类型：
--
作者：
Goodman, Matthew O.;Cade, Brian E.;Shah, Neomi A.;Huang, Tianyi;Dashti, Hassan S.;Saxena, Richa;Rutter, Martin K.;Libby, Peter;Sofer, Tamar;Redline, Susan
关键词：
阻塞性睡眠呼吸暂停 (OSA) 及其特征，例如慢性间歇性缺氧 (IH)，可能会不同程度地影响冠状动脉疾病 (CAD) 发病机制中的特定分子途径和过程，并影响 CAD 事件的后续风险和严重程度。特别是，竞争性不利（例如炎症）和保护（例如增加冠状动脉侧支血流量）机制可能起作用，但仍知之甚少。我们假设，选定分子途径中的常见遗传变异以途径依赖性方式对患有和不患有 OSA 的个体发生 CAD 事件的可能性产生不同的影响。我们从英国生物银行中选择了 471,877 名参与者的横截面样本，其中 4,974 人确定患有 OSA，25,988 人患有 CAD，711 人患有两者。我们根据 CARDIoGRAMplusC4D 全基因组关联研究 (GWAS) 中评估的 660 万个常见变异，计算了 CAD 的途径特异性多基因风险评分 (PS-PRS)，并使用功能基因组数据库对特定基因和途径进行了注释。根据先前涉及 IH 和 CAD 的证据，我们测试了 PS-PRS 的 HIF-1、VEGF、NFκB 和 TNF 信号通路。在多变量调整逻辑广义相加模型中，KEGG VEGF 通路（39 个基因）的 PS-PRS 升高与 OSA 中的 CAD 保护相关（交互比值比 0.86，p = 6E-04）。相比之下，全基因组 CAD PRS 没有显示与 OSA 存在统计相互作用的证据。我们发现证据表明，患有和不患有 OSA 的个体之间 CAD 的途径特异性遗传风险存在差异，其质量途径依赖于途径。这些结果提供了证据，表明基因与环境的相互作用会影响 OSA 患者某些途径的 CAD 风险，但全基因组 PRS 未能很好地捕捉到这一效应。这需要进一步研究 OSA 如何在分子水平上与遗传风险相互作用，并建议最终根据个体途径特异性遗传风险概况进行个性化 OSA 治疗以降低 CAD 风险。
Obstructive sleep apnea (OSA) and its features, such as chronic intermittent hypoxia (IH), may differentially affect specific molecular pathways and processes in the pathogenesis of coronary artery disease (CAD) and influence the subsequent risk and severity of CAD events. In particular, competing adverse (e.g. inflammatory) and protective (e.g. increased coronary collateral blood flow) mechanisms may operate, but remain poorly understood. We hypothesize that common genetic variation in selected molecular pathways influences the likelihood of CAD events differently in individuals with and without OSA, in a pathway-dependent manner. We selected a cross-sectional sample of 471,877 participants from the UK Biobank, with 4,974 ascertained to have OSA, 25,988 to have CAD, and 711 to have both. We calculated pathway-specific polygenic risk scores (PS-PRS) for CAD, based on 6.6 million common variants evaluated in the CARDIoGRAMplusC4D genome-wide association study (GWAS), annotated to specific genes and pathways using functional genomics databases. Based on prior evidence of involvement with IH and CAD, we tested PS-PRS for the HIF-1, VEGF, NFκB and TNF signaling pathways. In a multivariable-adjusted logistic generalized additive model, elevated PS-PRSs for the KEGG VEGF pathway (39 genes) associated with protection for CAD in OSA (interaction odds ratio 0.86, p = 6E-04). By contrast, the genome-wide CAD PRS did not show evidence of statistical interaction with OSA. We find evidence that pathway-specific genetic risk of CAD differs between individuals with and without OSA in a qualitatively pathway-dependent manner. These results provide evidence that gene-by-environment interaction influences CAD risk in certain pathways among people with OSA, an effect that is not well-captured by the genome-wide PRS. This invites further study of how OSA interacts with genetic risk at the molecular level, and suggests eventual personalization of OSA treatment to reduce CAD risk according to individual pathway-specific genetic risk profiles.