Institute of Cardiovascular Science, Faculty of Population Health Science (R.S.P., A.F.S., L.J.H., K.D., J.D., A.D.H., F.W.A.).
Bart's Heart Centre, St Bartholomew's Hospital, London, United Kingdom (R.S.P., J.D., A. Timmis).
Circ Genom Precis Med. 2019 Apr;12(4):e002471. doi: 10.1161/CIRCGEN.119.002471. Epub 2019 Mar 21.
Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.
A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.
Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).
In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.
染色体 9p21 上的遗传变异是冠心病（CHD）的公认风险因素。然而，其对疾病进展和随后事件的影响尚不清楚，这引发了对其用于分层残余风险的价值的质疑。
在基线时患有已确诊 CHD 的 103715 名欧洲人中，测试了染色体 9p21 上的一个变体（rs1333049）与随后的事件之间的关联，这些患者来自 GENIUS-CHD（随后发生的冠心病的遗传学）联合会（73.1%为男性，平均年龄为 62.9 岁）。主要结局是在有可用结局数据的 93115 名参与者中，有 13040 名参与者发生了随后的 CHD 死亡或心肌梗死（CHD 死亡/心肌梗死）。通过与来自包括 47222 例 CHD 病例和 122264 例无 CHD 对照的 CARDIoGRAMplusC4D 联合会（冠状动脉疾病全基因组复制和荟萃分析[CARDIoGRAM]加冠状动脉疾病[C4D]遗传学）的病例/对照风险进行比较，评估了效应估计值。
荟萃分析显示，在基线时患有已确诊 CHD 的患者中，染色体 9p21 与 CHD 死亡/心肌梗死的主要结局之间没有显著关联（GENIUS-CHD 比值比，1.02；95%置信区间，0.99-1.05）。这与在 CARDIoGRAMPlusC4D 中的强烈关联形成对比，比值比为 1.20；95%置信区间，1.18-1.22；与 GENIUS-CHD 估计值相比，交互作用 P<0.001。同样，对于其他随后的结局，包括全因死亡，也没有明确的关联，尽管我们发现染色体 9p21 与随后的血运重建之间存在适度的正相关（比值比，1.07；95%置信区间，1.04-1.09）。
与比较 CHD 患者与无疾病对照的研究相比，当所有个体在基线时均患有 CHD 时，我们发现染色体 9p21 上的遗传变异与随后发生的急性 CHD 事件的风险之间没有明显关联。然而，与随后的血运重建的关联可能支持染色体 9p21 促进动脉粥样硬化发展的假设机制。
