Genetic associations of cardiovascular risk genes in European patients with coronary artery spasm.
Cardiac biomarker
Cardiovascular
Coronary artery spasm
Endothelin-1
Genetic variants
Journal
Clinical research in cardiology : official journal of the German Cardiac Society
ISSN: 1861-0692
Titre abrégé: Clin Res Cardiol
Pays: Germany
ID NLM: 101264123
Informations de publication
Date de publication:
18 Apr 2024
18 Apr 2024
Historique:
received:
20
11
2023
accepted:
27
03
2024
medline:
18
4
2024
pubmed:
18
4
2024
entrez:
18
4
2024
Statut:
aheadofprint
Résumé
Coronary artery spasm (CAS) is a frequent finding in patients presenting with angina pectoris. Although the pathogenesis of CAS is incompletely understood, previous studies suggested a genetic contribution. Our study aimed to elucidate genetic variants in a cohort of European patients with angina and unobstructed coronary arteries who underwent acetylcholine (ACh) provocation testing. A candidate association analysis of 208 genes previously associated with cardiovascular conditions was performed using genotyped and imputed variants in patients grouped in epicardial (focal, diffuse) CAS (n = 119) and microvascular CAS (n = 87). Patients with a negative ACh test result (n = 45) served as controls. We found no association below the genome-wide significance threshold of p < 5 × 10 In summary, we suggest EDN1 as potential genetic risk loci for patients with diffuse epicardial CAS, and European ancestry. Plasma ET-1 levels may serve as a potential cardiac marker.
Sections du résumé
BACKGROUND
BACKGROUND
Coronary artery spasm (CAS) is a frequent finding in patients presenting with angina pectoris. Although the pathogenesis of CAS is incompletely understood, previous studies suggested a genetic contribution. Our study aimed to elucidate genetic variants in a cohort of European patients with angina and unobstructed coronary arteries who underwent acetylcholine (ACh) provocation testing.
METHODS
METHODS
A candidate association analysis of 208 genes previously associated with cardiovascular conditions was performed using genotyped and imputed variants in patients grouped in epicardial (focal, diffuse) CAS (n = 119) and microvascular CAS (n = 87). Patients with a negative ACh test result (n = 45) served as controls.
RESULTS
RESULTS
We found no association below the genome-wide significance threshold of p < 5 × 10
CONCLUSIONS
CONCLUSIONS
In summary, we suggest EDN1 as potential genetic risk loci for patients with diffuse epicardial CAS, and European ancestry. Plasma ET-1 levels may serve as a potential cardiac marker.
Identifiants
pubmed: 38635033
doi: 10.1007/s00392-024-02446-x
pii: 10.1007/s00392-024-02446-x
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Deutsche Herzstiftung
ID : FF19/290
Informations de copyright
© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Camici PG, Crea F (2007) Coronary microvascular dysfunction. N Engl J Med 356:830–840. https://doi.org/10.1056/NEJMra061889
doi: 10.1056/NEJMra061889
pubmed: 17314342
Cheng TO, Bashour T, Kelser GA et al (1973) Variant angina of prinzmetal with normal coronary arteriograms: a variant of the variant. Circulation 47:476–485. https://doi.org/10.1161/01.CIR.47.3.476
doi: 10.1161/01.CIR.47.3.476
pubmed: 4632501
Crea F, Camici PG, Bairey Merz CN (2014) Coronary microvascular dysfunction: an update. Eur Heart J 35:1101–1111. https://doi.org/10.1093/eurheartj/eht513
doi: 10.1093/eurheartj/eht513
pubmed: 24366916
Ford TJ, Stanley B, Good R et al (2018) Stratified medical therapy using invasive coronary function testing in angina. J Am Coll Cardiol 72:2841–2855. https://doi.org/10.1016/j.jacc.2018.09.006
doi: 10.1016/j.jacc.2018.09.006
pubmed: 30266608
Ong P, Safdar B, Seitz A et al (2020) Diagnosis of coronary microvascular dysfunction in the clinic. Cardiovasc Res 116:841–855. https://doi.org/10.1093/cvr/cvz339
doi: 10.1093/cvr/cvz339
pubmed: 31904824
Sechtem U, Brown D, Godo S et al (2020) Coronary microvascular dysfunction in stable ischaemic heart disease (non-obstructive coronary artery disease and obstructive coronary artery disease). Cardiovasc Res 116:771–786. https://doi.org/10.1093/cvr/cvaa005
doi: 10.1093/cvr/cvaa005
pubmed: 31958128
Ford TJ, Yii E, Sidik N et al (2019) Ischemia and no obstructive coronary artery disease: prevalence and correlates of coronary vasomotion disorders. Circ Cardiovasc Interv 12:e008126. https://doi.org/10.1161/CIRCINTERVENTIONS.119.008126
doi: 10.1161/CIRCINTERVENTIONS.119.008126
pubmed: 31833416
pmcid: 6924940
Beltrame JF, Crea F, Kaski JC et al (2015) International standardization of diagnostic criteria for vasospastic angina. Eur Heart J 2565–2568. https://doi.org/10.1093/eurheartj/ehv351
Ong P, Camici PG, Beltrame JF et al (2018) International standardization of diagnostic criteria for microvascular angina. Int J Cardiol 250:16–20. https://doi.org/10.1016/j.ijcard.2017.08.068
doi: 10.1016/j.ijcard.2017.08.068
pubmed: 29031990
Beller GA (1989) Calcium antagonists in the treatment of Prinzmetal’s angina and unstable angina pectoris. Circulation 80:IV78-87
pubmed: 2574642
Seitz A, Morár N, Pirozzolo G et al (2020) Prognostic implications of coronary artery stenosis and coronary spasm in patients with stable angina: 5-year follow-up of the Abnormal COronary VAsomotion in patients with stable angina and unobstructed coronary arteries (ACOVA) study. Coron Artery Dis 31:530–537. https://doi.org/10.1097/MCA.0000000000000876
doi: 10.1097/MCA.0000000000000876
pubmed: 32168049
Erdmann J, Kessler T, Munoz Venegas L, Schunkert H (2018) A decade of genome-wide association studies for coronary artery disease: the challenges ahead. Cardiovasc Res. https://doi.org/10.1093/cvr/cvy084
doi: 10.1093/cvr/cvy084
pubmed: 29617720
Mizuno Y, Harada E, Morita S et al (2015) East Asian variant of aldehyde dehydrogenase 2 is associated with coronary spastic angina: possible roles of reactive aldehydes and implications of alcohol flushing syndrome. Circulation 131:1665–1673. https://doi.org/10.1161/CIRCULATIONAHA.114.013120
doi: 10.1161/CIRCULATIONAHA.114.013120
pubmed: 25759460
Takeuchi F, Yokota M, Yamamoto K et al (2012) Genome-wide association study of coronary artery disease in the Japanese. Eur J Hum Genet 20:333–340. https://doi.org/10.1038/ejhg.2011.184
doi: 10.1038/ejhg.2011.184
pubmed: 21971053
Yoshimura M, Yasue H, Nakayama M et al (1998) A missense Glu298Asp variant in the endothelial nitric oxide synthase gene is associated with coronary spasm in the Japanese. Hum Genet 103:65–69
doi: 10.1007/s004390050785
pubmed: 9737779
Nakayama M, Yasue H, Yoshimura M et al (1999) T
doi: 10.1161/01.CIR.99.22.2864
pubmed: 10359729
Kaneda H, Taguchi J, Kuwada Y et al (2006) Coronary artery spasm and the polymorphisms of the endothelial nitric oxide synthase gene. Circ J 70:409–413. https://doi.org/10.1253/circj.70.409
doi: 10.1253/circj.70.409
pubmed: 16565556
Yoo S-Y, Kim J, Cheong S et al (2012) Rho-associated kinase 2 polymorphism in patients with vasospastic angina. Korean Circ J 42:406–413. https://doi.org/10.4070/kcj.2012.42.6.406
doi: 10.4070/kcj.2012.42.6.406
pubmed: 22787471
pmcid: 3390426
Ong P, Pirozzolo G, Athanasiadis A, Sechtem U (2018) Epicardial coronary spasm in women with angina pectoris and unobstructed coronary arteries is linked with a positive family history: an observational study. Clin Ther 40:1584–1590. https://doi.org/10.1016/j.clinthera.2018.07.015
doi: 10.1016/j.clinthera.2018.07.015
pubmed: 30122309
Kessler T, Vilne B, Schunkert H (2016) The impact of genome-wide association studies on the pathophysiology and therapy of cardiovascular disease. EMBO Mol Med 8:688–701. https://doi.org/10.15252/emmm.201506174
doi: 10.15252/emmm.201506174
pubmed: 27189168
pmcid: 4931285
Ong P, Athanasiadis A, Sechtem U (2016) Intracoronary acetylcholine provocation testing for assessment of coronary vasomotor disorders. J Vis Exp 54295. https://doi.org/10.3791/54295
Gomes AM, Winter S, Klein K et al (2009) Pharmacogenomics of human liver cytochrome P450 oxidoreductase: multifactorial analysis and impact on microsomal drug oxidation. Pharmacogenomics 10:579–599. https://doi.org/10.2217/pgs.09.7
doi: 10.2217/pgs.09.7
pubmed: 19374516
Das S, Forer L, Schönherr S et al (2016) Next-generation genotype imputation service and methods. Nat Genet 48:1284–1287. https://doi.org/10.1038/ng.3656
doi: 10.1038/ng.3656
pubmed: 27571263
pmcid: 5157836
Purcell S, Neale B, Todd-Brown K et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575. https://doi.org/10.1086/519795
doi: 10.1086/519795
pubmed: 17701901
pmcid: 1950838
Marchini J, Howie B (2010) Genotype imputation for genome-wide association studies. Nat Rev Genet 11:499–511. https://doi.org/10.1038/nrg2796
doi: 10.1038/nrg2796
pubmed: 20517342
Tremmel R (2021) ggfastman, fast manhattenplots using ggplot2, https://doi.org/10.5281/zenodo.10656742
Lamparter D, Marbach D, Rueedi R et al (2016) Fast and rigorous computation of gene and pathway scores from SNP-based summary statistics. PLOS Comput Biol 12:e1004714. https://doi.org/10.1371/journal.pcbi.1004714
doi: 10.1371/journal.pcbi.1004714
pubmed: 26808494
pmcid: 4726509
Ionita-Laza I, Lee S, Makarov V et al (2013) Sequence kernel association tests for the combined effect of rare and common variants. Am J Hum Genet 92:841–853. https://doi.org/10.1016/j.ajhg.2013.04.015
doi: 10.1016/j.ajhg.2013.04.015
pubmed: 23684009
pmcid: 3675243
Sinnwell J, Schaid D haplo.stats: statistical analysis of haplotypes with traits and covariates when linkage phase is ambiguous. R package version 1.7.9. https://CRAN.R-project.org/package=haplo.stats
Ong P, Athanasiadis A, Borgulya G et al (2014) Clinical usefulness, angiographic characteristics, and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive white patients with unobstructed coronary arteries. Circulation 129:1723–1730. https://doi.org/10.1161/CIRCULATIONAHA.113.004096
doi: 10.1161/CIRCULATIONAHA.113.004096
pubmed: 24573349
Kessler T, Wobst J, Wolf B et al (2017) Functional characterization of the GUCY1A3 coronary artery disease risk locus. Circulation 136:476–489. https://doi.org/10.1161/CIRCULATIONAHA.116.024152
doi: 10.1161/CIRCULATIONAHA.116.024152
pubmed: 28487391
pmcid: 5560301
Kessler T, Wolf B, Eriksson N et al (2019) Association of the coronary artery disease risk gene GUCY1A3 with ischaemic events after coronary intervention. Cardiovasc Res 115:1512–1518. https://doi.org/10.1093/cvr/cvz015
doi: 10.1093/cvr/cvz015
pubmed: 30768153
Hendrix P, Foreman PM, Harrigan MR et al (2017) The role of endothelial nitric oxide synthase −786 T/C polymorphism in cardiac instability following aneurysmal subarachnoid hemorrhage. Nitric Oxide 71:52–56. https://doi.org/10.1016/j.niox.2017.10.008
doi: 10.1016/j.niox.2017.10.008
pubmed: 29079038
Martínez Pereyra V, Hubert A, Seitz A et al (2020) Epicardial and microvascular coronary spasm in the same patient?—acetylcholine testing pointing towards a common pathophysiological background. Coron Artery Dis 31:398–399. https://doi.org/10.1097/MCA.0000000000000829
doi: 10.1097/MCA.0000000000000829
pubmed: 31658150
Tanigawa Y, Qian J, Venkataraman G et al (2022) Significant sparse polygenic risk scores across 813 traits in UK Biobank. PLOS Genet 18:e1010105. https://doi.org/10.1371/journal.pgen.1010105
doi: 10.1371/journal.pgen.1010105
pubmed: 35324888
pmcid: 8946745
Ford TJ, Corcoran D, Padmanabhan S et al (2020) Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction. Eur Heart J 41:3239–3252. https://doi.org/10.1093/eurheartj/ehz915
doi: 10.1093/eurheartj/ehz915
pubmed: 31972008
pmcid: 7557475
Gupta RM, Hadaya J, Trehan A et al (2017) A genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression. Cell 170:522-533.e15. https://doi.org/10.1016/j.cell.2017.06.049
doi: 10.1016/j.cell.2017.06.049
pubmed: 28753427
pmcid: 5785707
Ota M, Nagafuchi Y, Hatano H et al (2021) Dynamic landscape of immune cell-specific gene regulation in immune-mediated diseases. Cell 184:3006-3021.e17. https://doi.org/10.1016/j.cell.2021.03.056
doi: 10.1016/j.cell.2021.03.056
pubmed: 33930287
Adlam D, Olson TM, Combaret N et al (2019) Association of the PHACTR1/EDN1 genetic locus with spontaneous coronary artery dissection. J Am Coll Cardiol 73:58–66. https://doi.org/10.1016/j.jacc.2018.09.085
doi: 10.1016/j.jacc.2018.09.085
pubmed: 30621952
pmcid: 10403154
Naya M, Aikawa T, Manabe O et al (2021) Elevated serum endothelin-1 is an independent predictor of coronary microvascular dysfunction in non-obstructive territories in patients with coronary artery disease. Heart Vessels 36:917–923. https://doi.org/10.1007/s00380-020-01767-x
doi: 10.1007/s00380-020-01767-x
pubmed: 33484293
Abraham GR, Morrow AJ, Oliveira J et al (2022) Mechanistic study of the effect of endothelin SNPs in microvascular angina - protocol of the PRIZE endothelin sub-study. Int J Cardiol Heart Vasc 39:100980. https://doi.org/10.1016/j.ijcha.2022.100980
doi: 10.1016/j.ijcha.2022.100980
pubmed: 35242999
pmcid: 8885580
Van Der Harst P, Verweij N (2018) Identification of 64 novel genetic loci provides an expanded view on the genetic architecture of coronary artery disease. Circ Res 122:433–443. https://doi.org/10.1161/CIRCRESAHA.117.312086
doi: 10.1161/CIRCRESAHA.117.312086
pubmed: 29212778
pmcid: 5805277
Seitz A, Gardezy J, Pirozzolo G et al (2020) Long-term follow-up in patients with stable angina and unobstructed coronary arteries undergoing intracoronary acetylcholine testing. JACC Cardiovasc Interv 13:1865–1876. https://doi.org/10.1016/j.jcin.2020.05.009
doi: 10.1016/j.jcin.2020.05.009
pubmed: 32739303
Jespersen L, Abildstrøm SZ, Hvelplund A, Prescott E (2013) Persistent angina: highly prevalent and associated with long-term anxiety, depression, low physical functioning, and quality of life in stable angina pectoris. Clin Res Cardiol 102:571–581. https://doi.org/10.1007/s00392-013-0568-z
doi: 10.1007/s00392-013-0568-z
pubmed: 23636227
Sahebkar A, Kotani K, Serban C et al (2015) Statin therapy reduces plasma endothelin-1 concentrations: a meta-analysis of 15 randomized controlled trials. Atherosclerosis 241:433–442. https://doi.org/10.1016/j.atherosclerosis.2015.05.022
doi: 10.1016/j.atherosclerosis.2015.05.022
pubmed: 26074317
Kabaklić A, Fras Z (2017) Moderate-dose atorvastatin improves arterial endothelial function in patients with angina pectoris and normal coronary angiogram: a pilot study. Arch Med Sci 4:827–836. https://doi.org/10.5114/aoms.2017.68238
doi: 10.5114/aoms.2017.68238