Polygenic risk score for ACE-inhibitor-associated cough based on the discovery of new genetic loci-Reference-Cited by-同舟云学术

Polygenic risk score for ACE-inhibitor-associated cough based on the discovery of new genetic loci

Published:2022-06-25 Issue:45 Volume:43 Page:4707-4718
ISSN:0195-668X
Container-title:European Heart Journal
language:en
Short-container-title:

Author:

Ghouse Jonas¹²^ORCID,Tragante Vinicius³^ORCID,Muhammad Ayesha⁴^ORCID,Ahlberg Gustav¹²^ORCID,Skov Morten W¹²,Roden Dan M⁴⁵^ORCID,Jonsdottir Ingileif³⁶⁷^ORCID,Andreasen Laura¹²^ORCID,Lundegaard Pia Rengtved¹²^ORCID,Trudsø Linea C¹²^ORCID,Banasik Karina⁸^ORCID,Brunak Søren⁸,Ostrowski Sisse R⁹¹⁰^ORCID,Torp-Pedersen Christian¹¹¹⁰^ORCID,Pedersen Ole V¹²¹⁰,Sørensen Erik⁹¹⁰,Køber Lars¹³¹⁰^ORCID,Iversen Kasper¹⁴¹⁰,Thorsteinsdottir Unnur³⁶^ORCID,Thorgeirsson Gudmundur³¹⁵^ORCID,Ullum Henrik¹⁶^ORCID,Gudbjartsson Daniel F³¹⁷,Mosley Jonathan D⁵^ORCID,Holm Hilma³^ORCID,Stefansson Kari³⁶^ORCID,Bundgaard Henning¹³¹⁰^ORCID,Olesen Morten Salling¹²,

Affiliation:

1. Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet , Building 9312, Henrik Harpestrengs Vej 4C, 2100 Copenhagen , Denmark

2. Laboratory for Molecular Cardiology, Department of Biomedical Sciences, University of Copenhagen , Copenhagen , Denmark

3. deCODE genetics/Amgen, Inc. , Reykjavik , Iceland

4. Vanderbilt Genetics Institute, Department of Medicine, Vanderbilt University Medical Center, and Vanderbilt Medical Scientist Training Program, Vanderbilt University , USA

5. Departments of Internal Medicine and Biomedical Informatics, Vanderbilt University Medical Center , Nashville, Tennessee , USA

6. Faculty of Medicine, University of Iceland , Iceland

7. Iceland Department of Immunology, Landspitali—The National University Hospital of Iceland , Reykjavik , Iceland

8. Translational Disease Systems Biology, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark

9. Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital , Copenhagen , Denmark

10. Department of Clinical Medicine, University of Copenhagen , Copenhagen , Denmark

11. Department of Cardiology, Aalborg University Hospital , Aalborg , Denmark

12. Department of Clinical Immunology, Næstved Hospital , Næstved , Denmark

13. Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, University of Copenhagen , Copenhagen , Denmark

14. Department of Cardiology, Copenhagen University Hospital, Herlev-Gentofte Hospital , Herlev , Denmark

15. Department of Medicine, Landspitali—The National University Hospital of Iceland , Reykjavik , Iceland

16. Statens Serum Institut , Copenhagen , Denmark

17. School of Engineering and Natural Sciences, University of Iceland , Reykjavik , Iceland

Abstract

Abstract Aims To search for sequence variants associated with ACEi discontinuation and to test their association with ACEi-associated adverse drug reactions (ADRs). Methods and results A genome-wide association study (GWAS) on ACEi discontinuation was conducted, including 33 959 ACEi-discontinuers and 44 041 controls. Cases were defined as persons who switched from an ACEi treatment to an angiotensin receptor blocker. Controls were defined as persons who continued ACEi treatment for at least 1 year. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed for ACEi discontinuation risk by mixed model regression analysis. Summary statistics from the individual cohorts were meta-analyzed with a fixed-effects model. To test for association with specific ACEi-associated ADRs, any genome-wide significant (P < 5 × 10-8) ACEi discontinuation variants was tested for association with ACEi-associated cough and angioedema. A polygenetic risk score (PRS) based on ACEi discontinuation GWAS data was constructed and tested for association with ACEi-associated cough and angioedema in two population-based samples. In total, seven genetic genome-wide loci were identified, of which six were previously unreported. The strongest association with ACEi discontinuation was at 20q13.3 (NTSR1; OR: 1.21; 95% CI: 1.17–1.24; P = 2.1 × 10–34). Five of seven lead variants were associated with ACEi-associated cough, whereas none were associated with ACEi-associated angioedema. The ACEi discontinuation PRS was associated with ACEi-associated cough in a dose–response manner but not with ACEi-associated angioedema. ACEi discontinuation was genetically correlated with important causes for cough, including gastro-esophageal reflux disease, allergic rhinitis, hay fever, and asthma, which indicates partly shared genetic underpinning between these traits. Conclusion This study showed the advantage of using prescription patterns to discover genetic links with ADRs. In total, seven genetic loci that associated with ACEi discontinuation were identified. There was evidence of a strong association between our ADR phenotype and ACEi-associated cough. Taken together, these findings increase insight into the pathophysiological processes that underlie ACEi-associated ADRs.

Funder

BRIDGE - Translational Excellence Programme

Broad Institute

CIDR

CTSA

Essentia Institute of Rural Health

Geisinger Clinic

Genotyping Centers

Group Health Cooperative

University of Washington

Icahn School of Medicine at Mount Sinai

Marshfield Clinic Research Foundation