Georgakis Marios K, Malik Rainer, El Bounkari Omar, Hasbani Natalie R, Li Jiang, Huffman Jennifer E, Shakt Gabrielle, Tack Reinier W P, Kimball Tamara N, Asare Yaw, Morrison Alanna C, Tsao Noah L, Judy Renae, Mitchell Braxton D, Xu Huichun, Montasser May E, Do Ron, Kenny Eimear E, Loos Ruth J F, Terry James G, Carr John Jeffrey, Bis Joshua C, Psaty Bruce M, Longstreth W T, Young Kendra A, Lutz Sharon M, Cho Michael H, Broome Jai, Khan Alyna T, Wang Fei Fei, Heard-Costa Nancy, Seshadri Sudha, Vasan Ramachandran S, Palmer Nicholette D, Freedman Barry I, Bowden Donald W, Yanek Lisa R, Kral Brian G, Becker Lewis C, Peyser Patricia A, Bielak Lawrence F, Ammous Farah, Carson April P, Hall Michael E, Raffield Laura M, Rich Stephen S, Post Wendy S, Tracy Russel P, Taylor Kent D, Guo Xiuqing, Mahaney Michael C, Curran Joanne E, Blangero John, Clarke Shoa L, Haessler Jeffrey W, Hu Yao, Assimes Themistocles L, Kooperberg Charles, Bernhagen Jürgen, Anderson Christopher D, Damrauer Scott M, Zand Ramin, Rotter Jerome I, de Vries Paul S, Dichgans Martin
Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU), Munich, Germany.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
medRxiv. 2024 Jun 26:2023.08.14.23294063. doi: 10.1101/2023.08.14.23294063.
Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.
Computationally predicted damaging or loss-of-function (REVEL>0.5) variants within were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n=1,062,595).
Carriers of 45 predicted damaging or loss-of-function variants (n=787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n=585, 0.15% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (Odds Ratio [OR]: 0.66 95% Confidence Interval [CI]: 0.54-0.81, p=6.1×10) and coronary artery disease (OR: 0.74 95%CI: 0.63-0.87, p=2.9×10) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers.
Carriers of an experimentally confirmed damaging variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.
先前的研究表明，趋化因子CCL2在动脉粥样硬化中发挥作用，CCL2是调控单核细胞运输的关键趋化因子。然而，靶向CCL2的同源受体CCR2是否能预防人类动脉粥样硬化性心血管疾病仍不清楚。
在来自454775名英国生物银行参与者的全外显子测序数据中，检测计算预测的有害或功能丧失（REVEL>0.5）变异，并在基因负担测试中检测其与心血管终点的关联。鉴于CCR2在单核细胞动员中的关键作用，将与较低单核细胞计数相关的变异优先进行实验验证。用这些变异转染的人类细胞对CCL2的反应在迁移和cAMP测定中进行测试。对经验证的有害变异进行检测，以确定其与心血管终点、动脉粥样硬化负担和血管危险因素的关联。在六个独立数据集（n=1062595）中重复显著关联。
45个预测的有害或功能丧失变异的携带者（n=787人）发生心肌梗死和冠状动脉疾病的风险较低。其中一个变异（M249K，n=585，占欧洲血统个体的0.15%）与较低的单核细胞计数以及对CCL2反应时下游信号传导和化学吸引的降低有关。虽然M249K与传统血管危险因素无关，但在英国生物银行和六个重复队列中，它始终与较低的心肌梗死风险（优势比[OR]：0.66，95%置信区间[CI]：0.54-0.81，p=6.1×10）和冠状动脉疾病风险（OR：0.74，95%CI：0.63-0.87，p=2.9×10）相关。在一项全表型关联研究中，没有证据表明M249K携带者感染风险更高。
经实验证实的有害变异携带者发生心肌梗死和冠状动脉疾病的终生风险较低，且没有更高的感染风险。我们的研究结果为靶向CCR2作为一种抗动脉粥样硬化方法的转化潜力提供了遗传学支持。
