Comorbidities of coronavirus disease 2019 (COVID-19)/coronary heart disease (CHD) pose great threats to disease outcomes, yet little is known about their shared pathology. The study aimed to examine whether comorbidities of COVID-19/CHD involved shared genetic pathology, as well as to clarify the shared genetic variants predisposing risks common to COVID-19 severity and CHD risks. By leveraging publicly available summary statistics, we assessed the genetically determined causality between COVID-19 and CHD with bidirectional Mendelian randomization. To further quantify the causality contributed by shared genetic variants, we interrogated their genetic correlation with the linkage disequilibrium score regression method. Bayesian colocalization analysis coupled with conditional/conjunctional false discovery rate analysis was applied to decipher the shared causal single nucleotide polymorphisms (SNPs). Briefly, we observed that the incident CHD risks post COVID-19 infection were partially determined by shared genetic variants. The shared genetic variants contributed to the causality at a proportion of 0.18 (95% CI 0.18–0.19) to 0.23 (95% CI 0.23–0.24). The SNP (rs10490770) located near LZTFL1 suggested direct causality (SNPs → COVID-19 → CHD), and SNPs in ABO (rs579459, rs495828), ILRUN(rs2744961), and CACFD1(rs4962153, rs3094379) may simultaneously influence COVID-19 severity and CHD risks. Five SNPs located near LZTFL1 (rs10490770), ABO (rs579459, rs495828), ILRUN (rs2744961), and CACFD1 (rs4962153, rs3094379) may simultaneously influence their risks. The current study suggested that there may be shared mechanisms predisposing to both COVID-19 severity and CHD risks. Genetic predisposition to COVID-19 is a causal risk factor for CHD, supporting that reducing the COVID-19 infection risk or alleviating COVID-19 severity among those with specific genotypes might reduce their subsequent CHD adverse outcomes. Meanwhile, the shared genetic variants identified may be of clinical implications for identifying the target population who are more vulnerable to adverse CHD outcomes post COVID-19 and may also advance treatments of ‘Long COVID-19.’

中文翻译：

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共同影响COVID-19和冠心病的遗传位点的鉴定

2019 年冠状病毒病 (COVID-19)/冠心病 (CHD) 的合并症对疾病结果构成巨大威胁，但人们对它们共同的病理学知之甚少。该研究旨在检查 COVID-19/CHD 合并症是否涉及共同的遗传病理学，并阐明导致 COVID-19 严重程度和 CHD 风险常见风险的共同遗传变异。通过利用公开的汇总统计数据，我们通过双向孟德尔随机化评估了 COVID-19 和 CHD 之间由基因决定的因果关系。为了进一步量化共享遗传变异所造成的因果关系，我们用连锁不平衡评分回归方法询问了它们的遗传相关性。贝叶斯共定位分析与条件/结合错误发现率分析相结合，用于破译共享的因果单核苷酸多态性 (SNP)。简而言之，我们观察到，COVID-19 感染后发生 CHD 的风险部分是由共享的基因变异决定的。共有的遗传变异对因果关系的影响比例为 0.18 (95% CI 0.18–0.19) 至 0.23 (95% CI 0.23–0.24)。位于 LZTFL1 附近的 SNP (rs10490770) 表明存在直接因果关系 (SNP → COVID-19 → CHD)，ABO (rs579459、rs495828)、ILRUN(rs2744961) 和 CACFD1(rs4962153、rs3094379) 中的 SNP 可能同时影响 COVID-19 的严重程度和冠心病风险。位于 LZTFL1 (rs10490770)、ABO (rs579459、rs495828)、ILRUN (rs2744961) 和 CACFD1 (rs4962153、rs3094379) 附近的 5 个 SNP 可能同时影响其风险。目前的研究表明，可能存在共同的机制导致 COVID-19 的严重程度和 CHD 风险。COVID-19 的遗传易感性是 CHD 的一个因果危险因素，这表明降低特定基因型患者的 COVID-19 感染风险或减轻 COVID-19 的严重程度可能会减少其随后的 CHD 不良后果。同时，所确定的共享遗传变异可能对确定在 COVID-19 后更容易遭受不良 CHD 后果的目标人群具有临床意义，并且还可能推进“长 COVID-19”的治疗。