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Int J Cardiol. 2019 Feb 1;276:212-217. doi: 10.1016/j.ijcard.2018.11.094. Epub 2018 Nov 17.

Effects of the coronary artery disease associated LPA and 9p21 loci on risk of aortic valve stenosis.

Author information

1
Klinik für Herz- und Kreislauferkrankungen, Deutsches Herzzentrum München, Technical University Munich, Munich, Germany.
2
Department of Cardiovascular Sciences, Cardiovascular Research Centre, NIHR Leicester Biomedical Research Centre University of Leicester, Leicester, United Kingdom.
3
Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom.
4
Department of Cardiology, Sahlgrenska University Hospital, Göteborg, Sweden.
5
Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
6
Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Stockholm, Karolinska University Hospital, Solna, Sweden.
7
Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Karolinska University Hospital, Solna, Sweden.
8
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, USA.
9
Department of Internal Medicine: Cardiology, University of Michigan, Ann Arbor, USA.
10
Department of Internal Medicine: Cardiology, University of Michigan, Ann Arbor, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, USA; Department of Human Genetics, University of Michigan, Ann Arbor, USA.
11
K.G. Jebsen Center for Genetic Epidemiology, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, NTNU, Norway; Dept. of public health and nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, NTNU, Norway; HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway.
12
Klinik für Herz- und Kreislauferkrankungen, Deutsches Herzzentrum München, Technical University Munich, Munich, Germany; Deutsches Zentrum für Herz- und Kreislauf-Forschung (DZHK) e.V. (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
13
Klinik für Herz- und Kreislauferkrankungen, Deutsches Herzzentrum München, Technical University Munich, Munich, Germany; Klinik für Kardiologie, St. Johannes Hospital, Dortmund, Germany.
14
Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom. Electronic address: c.c.lang@dundee.ac.uk.
15
Klinik für Herz- und Kreislauferkrankungen, Deutsches Herzzentrum München, Technical University Munich, Munich, Germany; Deutsches Zentrum für Herz- und Kreislauf-Forschung (DZHK) e.V. (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany; Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria. Electronic address: christian.hengstenberg@meduniwien.ac.at.
16
Department of Cardiovascular Sciences, Cardiovascular Research Centre, NIHR Leicester Biomedical Research Centre University of Leicester, Leicester, United Kingdom. Electronic address: njs@leicester.ac.uk.

Abstract

BACKGROUND:

Aortic valve stenosis (AVS) and coronary artery disease (CAD) have a significant genetic contribution and commonly co-exist. To compare and contrast genetic determinants of the two diseases, we investigated associations of the LPA and 9p21 loci, i.e. the two strongest CAD risk loci, with risk of AVS.

METHODS:

We genotyped the CAD-associated variants at the LPA (rs10455872) and 9p21 loci (rs1333049) in the GeneCAST (Genetics of Calcific Aortic STenosis) Consortium and conducted a meta-analysis for their association with AVS. Cases and controls were stratified by CAD status. External validation of findings was undertaken in five cohorts including 7880 cases and 851,152 controls.

RESULTS:

In the meta-analysis including 4651 cases and 8231 controls the CAD-associated allele at the LPA locus was associated with increased risk of AVS (OR 1.37; 95%CI 1.24-1.52, p = 6.9 × 10-10) with a larger effect size in those without CAD (OR 1.53; 95%CI 1.31-1.79) compared to those with CAD (OR 1.27; 95%CI 1.12-1.45). The CAD-associated allele at 9p21 was associated with a trend towards lower risk of AVS (OR 0.93; 95%CI 0.88-0.99, p = 0.014). External validation confirmed the association of the LPA risk allele with risk of AVS (OR 1.37; 95%CI 1.27-1.47), again with a higher effect size in those without CAD. The small protective effect of the 9p21 CAD risk allele could not be replicated (OR 0.98; 95%CI 0.95-1.02).

CONCLUSIONS:

Our study confirms the association of the LPA locus with risk of AVS, with a higher effect in those without concomitant CAD. Overall, 9p21 was not associated with AVS.

KEYWORDS:

9p21; Aortic valve stenosis; Lipoprotein (a); Risk factors; Valvular heart disease

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