Genetic variants associated with syncope implicate neural and autonomic processes

Aegisdottir, Hildur M; Þórólfsdóttir, Rósa B.; Sveinbjörnsson, Garðar; Stefansson, Olafur A.; Gunnarsson, Bjarni; Tragante, Vinicius; Þorleifsson, Guðmar; Stefánsdóttir, Lilja; Thorgeirsson, Thorgeir E.; Ferkingstad, Egil; Sulem, Patrick; Norddahl, Gudmundur L.; Rutsdottir, Gudrun; Banasik, Karina; Christensen, Alex Hørby; Mikkelsen, Christina; Pedersen, Ole Birger; Brunak, Søren; Bruun, Mie Topholm; Erikstrup, Christian; Jacobsen, Rikke Louise; Nielsen, Kaspar René; Sørensen, Erik; Frigge, Michael L.; Hjorleifsson, Kristjan E; Ívarsdóttir, Erna V.; Helgadóttir, Anna; Grétarsdóttir, Sólveig; Steinthórsdóttir, Valgerður; Oddsson, Ásmundur; Halldorsson, Gisli H.; Jones, David A.; Anderson, Jeffrey L.; Knowlton, Kirk U.; Nadauld, Lincoln; Þorgeirsson, Guðmundur; Bundgaard, Henning; Arnar, Davíð O.; Þorsteinsdóttir, Unnur; Guðbjartsson, Daníel F.; Ostrowski, Sisse Rye; Hólm, Hilma; Stefánsson, Kāri

doi:10.1093/eurheartj/ehad016

Cited by 7 publications

(2 citation statements)

References 75 publications

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“…The copyright holder for this preprint this version posted August 16, 2023. ; https://doi.org/10.1101/2023.08.14.23294063 doi: medRxiv preprint 20 described in Helgadottir et al, 2007 41 and genotyping and statistical analysis as described in Aegisdottir et al 2023. 42…”

Section: (Which Was Not Certified By Peer Review)mentioning

confidence: 99%

Rare damagingCCR2variants are associated with lower lifetime cardiovascular risk

Georgakis

Malik²,

Hasbani

et al. 2023

Preprint

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Background: 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. Methods: 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 CCR2 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. Results: A total of 45 predicted LoF or damaging missense variants were identified in the CCR2 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 CCR2 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 (ORUKB: 0.62 95%CI: 0.39-0.96; ORexternal: 0.64 95%CI: 0.34-1.19; ORpooled: 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 CCR2 variants. Conclusions: Heterozygous carriers of damaging CCR2 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.

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Section: (Which Was Not Certified By Peer Review)mentioning

confidence: 99%

Rare damagingCCR2variants are associated with lower lifetime cardiovascular risk

Georgakis

Malik²,

Hasbani

et al. 2023

Preprint

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“…Finally, as for genetic basis of reflex syncope, a positive family history can be identified in a significant proportion of patients, 16 , 17 and recent genetic association study has suggested that syncope patients may share some genetic susceptibility to lower BP and altered autonomic control of circulation. 18 …”

Section: Epidemiology and Mechanismsmentioning

confidence: 99%

Twenty-five years of research on syncope

Fedorowski,

Kulakowski,

Brignole

et al. 2023

Europace

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Over the last 25 years, the Europace journal has greatly contributed to dissemination of research and knowledge in the field of syncope. More than 400 manuscripts have been published in the journal. They undoubtedly improved our understanding of syncope. This symptom is now clearly differentiated from other forms of transient loss of consciousness. The critical role of vasodepression and/or cardioinhibition as final mechanisms of reflex syncope is emphasized. Current diagnostic approach sharply separates between cardiac and autonomic pathways. Physiologic insights have been translated, through rigorously designed clinical trials, into non-pharmacological or pharmacological interventions and interventional therapies. The following manuscript is intended to give the reader the current state of the art of knowledge of syncope by highlighting landmark contributions of the Europace journal.

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Have we found the genetic signature for vasovagal syncope?

Sheldon

Gerull

2023

European Heart Journal

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Genetic variants associated with syncope implicate neural and autonomic processes

Cited by 7 publications

References 75 publications

Rare damagingCCR2variants are associated with lower lifetime cardiovascular risk

Rare damagingCCR2variants are associated with lower lifetime cardiovascular risk

Twenty-five years of research on syncope

Have we found the genetic signature for vasovagal syncope?

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