Top

18-04-2024 | Original Paper

Genetic associations of cardiovascular risk genes in European patients with coronary artery spasm

Authors: Roman Tremmel, Valeria Martínez Pereyra, Incifer Broders, Elke Schaeffeler, Per Hoffmann, Markus M. Nöthen, Raffi Bekeredjian, Udo Sechtem, Matthias Schwab, Peter Ong

Published in: Clinical Research in Cardiology

Abstract

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

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

We found no association below the genome-wide significance threshold of p < 5 × 10⁻⁸, thus not confirming variants in ALDH2, NOS3, and ROCK2 previously reported in CAS patients of Asian ancestry. However, the analysis identified suggestive associations (p < 10⁻⁰⁵) for the groups of focal epicardial CAS (CDH13) and diffuse epicardial CAS (HDAC9, EDN1). Downstream analysis of the potential EDN1 risk locus showed that CAS patients have significantly increased plasma endothelin-1 levels (ET-1) compared to controls. An EDN1 haplotype comprising rs9349379 and rs2070698 was significantly associated to ET-1 levels (p = 0.01).

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.

Graphical Abstract

Available only for authorised users

Camici PG, Crea F (2007) Coronary microvascular dysfunction. N Engl J Med 356:830–840. https://doi.org/10.1056/NEJMra061889CrossRefPubMed

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.47.3.476CrossRefPubMed

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/eht513CrossRefPubMed

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.2018.09.006CrossRefPubMed

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/cvz339CrossRefPubMed

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/cvaa005CrossRefPubMed

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.119.008126CrossRefPubMedPubMedCentral

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.2017.08.068CrossRefPubMed

10.

Beller GA (1989) Calcium antagonists in the treatment of Prinzmetal’s angina and unstable angina pectoris. Circulation 80:IV78-87PubMed

11.

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.0000000000000876CrossRefPubMed

12.

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/cvy084CrossRefPubMed

13.

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.114.013120CrossRefPubMed

14.

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.2011.184CrossRefPubMed

15.

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 103:65–69CrossRefPubMed

16.

Nakayama M, Yasue H, Yoshimura M et al (1999) T ⁻⁷⁸⁶ →C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation 99:2864–2870. https://doi.org/10.1161/01.CIR.99.22.2864CrossRefPubMed

17.

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.70.409CrossRefPubMed

18.

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.2012.42.6.406CrossRefPubMedPubMedCentral

19.

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.2018.07.015CrossRefPubMed

20.

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.201506174CrossRefPubMedPubMedCentral

21.

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

22.

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.09.7CrossRefPubMed

23.

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.3656CrossRefPubMedPubMedCentral

24.

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/10.1086/519795CrossRefPubMedPubMedCentral

25.

Marchini J, Howie B (2010) Genotype imputation for genome-wide association studies. Nat Rev Genet 11:499–511. https://doi.org/10.1038/nrg2796CrossRefPubMed

26.

Tremmel R (2021) ggfastman, fast manhattenplots using ggplot2, https://doi.org/10.5281/zenodo.10656742

27.

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.1004714CrossRefPubMedPubMedCentral

28.

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.2013.04.015CrossRefPubMedPubMedCentral

29.

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

30.

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.113.004096CrossRefPubMed

31.

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.116.024152CrossRefPubMedPubMedCentral

32.

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/cvz015CrossRefPubMed

33.

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.2017.10.008CrossRefPubMed

34.

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.0000000000000829CrossRefPubMed

35.

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.1010105CrossRefPubMedPubMedCentral

36.

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/ehz915CrossRefPubMedPubMedCentral

37.

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.2017.06.049CrossRefPubMedPubMedCentral

38.

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.2021.03.056CrossRefPubMed

39.

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.2018.09.085CrossRefPubMedPubMedCentral

40.

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-xCrossRefPubMed

41.

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.2022.100980CrossRefPubMedPubMedCentral

42.

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.117.312086CrossRefPubMedPubMedCentral

43.

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.2020.05.009CrossRefPubMed

44.

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-zCrossRefPubMed

45.

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.2015.05.022CrossRefPubMed

46.

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.2017.68238CrossRef

Title: Genetic associations of cardiovascular risk genes in European patients with coronary artery spasm
Authors: Roman Tremmel
Valeria Martínez Pereyra
Incifer Broders
Elke Schaeffeler
Per Hoffmann
Markus M. Nöthen
Raffi Bekeredjian
Udo Sechtem
Matthias Schwab
Peter Ong
Publication date: 18-04-2024
Publisher: Springer Berlin Heidelberg
Published in: Clinical Research in Cardiology
Print ISSN: 1861-0684
Electronic ISSN: 1861-0692
DOI: https://doi.org/10.1007/s00392-024-02446-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Genetic associations of cardiovascular risk genes in European patients with coronary artery spasm

Abstract

Background

Methods

Results

Conclusions

Graphical Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Graphical Abstract

Please log in to get access to this content