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Carriers of rare damaging genetic variants are at lower risk of atherosclerotic disease.

TitleCarriers of rare damaging genetic variants are at lower risk of atherosclerotic disease.
Publication TypeJournal Article
Year of Publication2023
AuthorsGeorgakis, MK, Malik, R, Hasbani, NR, Shakt, G, Morrison, AC, Tsao, NL, Judy, R, Mitchell, BD, Xu, H, Montasser, ME, Do, R, Kenny, EE, Loos, RJF, Terry, JG, Carr, JJeffrey, Bis, JC, Psaty, BM, Longstreth, WT, Young, KA, Lutz, SM, Cho, MH, Broome, J, Khan, AT, Wang, FFei, Heard-Costa, N, Seshadri, S, Vasan, RS, Palmer, ND, Freedman, BI, Bowden, DW, Yanek, LR, Kral, BG, Becker, LC, Peyser, PA, Bielak, LF, Ammous, F, Carson, AP, Hall, ME, Raffield, LM, Rich, SS, Post, WS, Tracy, RP, Taylor, KD, Guo, X, Mahaney, MC, Curran, JE, Blangero, J, Clarke, SL, Haessler, JW, Hu, Y, Assimes, TL, Kooperberg, C, Damrauer, SM, Rotter, JI, de Vries, PS, Dichgans, M
Date Published2023 Aug 16
Abstract<p><b>BACKGROUND: </b>The CCL2/CCR2 axis governs monocyte trafficking and recruitment to atherosclerotic lesions. Human genetic analyses and population-based studies support an association between circulating CCL2 levels and atherosclerosis. Still, it remains unknown whether pharmacological targeting of CCR2, the main CCL2 receptor, would provide protection against human atherosclerotic disease.</p><p><b>METHODS: </b>In whole-exome sequencing data from 454,775 UK Biobank participants (40-69 years), we identified predicted loss-of-function (LoF) or damaging missense (REVEL score >0.5) variants within the gene. We prioritized variants associated with lower monocyte count (p<0.05) and tested associations with vascular risk factors and risk of atherosclerotic disease over a mean follow-up of 14 years. The results were replicated in a pooled cohort of three independent datasets (TOPMed, deCODE and Penn Medicine BioBank; total n=441,445) and the effect of the most frequent damaging variant was experimentally validated.</p><p><b>RESULTS: </b>A total of 45 predicted LoF or damaging missense variants were identified in the gene, 4 of which were also significantly associated with lower monocyte count, but not with other white blood cell counts. Heterozygous carriers of these variants were at a lower risk of a combined atherosclerosis outcome, showed a lower burden of atherosclerosis across four vascular beds, and were at a lower lifetime risk of coronary artery disease and myocardial infarction. There was no evidence of association with vascular risk factors including LDL-cholesterol, blood pressure, glycemic status, or C-reactive protein. Using a cAMP assay, we found that cells transfected with the most frequent damaging variant (3:46358273:T:A, M249K, 547 carriers, frequency: 0.14%) show a decrease in signaling in response to CCL2. The associations of the M249K variant with myocardial infarction were consistent across cohorts (OR : 0.62 95%CI: 0.39-0.96; OR : 0.64 95%CI: 0.34-1.19; OR : 0.64 95%CI: 0.45-0.90). In a phenome-wide association study, we found no evidence for higher risk of common infections or mortality among carriers of damaging variants.</p><p><b>CONCLUSIONS: </b>Heterozygous carriers of damaging variants have a lower burden of atherosclerosis and lower lifetime risk of myocardial infarction. In conjunction with previous evidence from experimental and epidemiological studies, our findings highlight the translational potential of CCR2-targeting as an atheroprotective approach.</p>
Alternate JournalmedRxiv
PubMed ID37645892
PubMed Central IDPMC10462211
ePub date: