Background and aims: Ample evidence links CCL2, a key chemokine governing monocyte trafficking, with atherosclerosis. However, it remains unknown whether targeting the CCL2 receptor CCR2 could provide protection against cardiovascular disease.
Methods: Computationally predicted damaging (REVEL>0.5) variants within CCR2 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 loss-of-function 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).
Results: Carriers of 45 predicted damaging CCR2 variants were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K) was associated with lower monocyte count and decreased 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: 0.66 95% Confidence Interval: 0.54-0.81,p=6.1x10-5) and coronary artery disease(Odds Ratio: 0.74 95% Confidence Interval: 0.62-0.87, p=2.9x10-4) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of higher infections risk among M249K carriers.
Conclusions: Carriers of an experimentally confirmed loss-of-function CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher infection risk. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.