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Nat Commun. 2018 Mar 7;9(1):987. doi: 10.1038/s41467-018-03252-6.

Genome-wide analysis yields new loci associating with aortic valve stenosis.

Author information

1
deCODE genetics/Amgen Inc., Reykjavik, 101, Iceland. anna.helgadottir@decode.is.
2
deCODE genetics/Amgen Inc., Reykjavik, 101, Iceland.
3
Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland.
4
Department of Cardiology, University of Groningen, University Medical Center Groningen, 9700 RB, Groningen, The Netherlands.
5
Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, 02142, MA, USA.
6
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, 48109, MI, USA.
7
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, 48109, MI, USA.
8
Cardiovascular Medicine Unit, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, 17176, Sweden.
9
Department of Bioinformatics, Technical University of Denmark, Copenhagen, 2800, Denmark.
10
Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, 22185, Sweden.
11
Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA.
12
Department of Internal Medicine, Division of Medical Genetics, University of Texas Health Science Center at Houston, Houston, 77030, TX, USA.
13
Childrens Hospital, Landspitali National University Hospital of Iceland, Reykjavik, 101, Iceland.
14
Department of Surgery and Cardiothoracic Surgery, Landspitali National University Hospital, Reykjavik, 101, Iceland.
15
Section of Cardiac Surgery, Department of Surgery, Yale University School of Medicine, New Haven, 06510, CT, USA.
16
Department of Clinical Biochemistry, Landspitali National University Hospital, Reykjavik, 101, Iceland.
17
Heilsugaeslan Solvangi, Hafnarfjördur, 220, Iceland.
18
Department of Family Medicine, University of Iceland, Reykjavik, 101, Iceland.
19
Department of Clinical Sciences, Lund University, Malmö, 22185, Sweden.
20
Department of Internal Medicine, Skåne University Hospital, Malmö, 22185, Sweden.
21
Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, 17176, Sweden.
22
HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, 7491, Norway.
23
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Norwegian University of Science and Technology, Trondheim, 7491, Norway.
24
Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI, 48105, USA.
25
Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, 48109, USA.
26
Department of Anesthesiology, University of Michigan, Ann Arbor, MI, 48105, USA.
27
Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA.
28
Medicine Services, Texas Heart Institute, St. Luke's Episcopal Hospital, Houston, TX, 77030, USA.
29
Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.
30
Massachusetts General Hospital, Harvard Medical School, Broad Institute of Harvard and MIT, Boston, MA, 02114, USA.
31
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA.
32
Department of Internal Medicine, Division of Cardiology, Landspitali National University Hospital of Iceland, Reykjavik, 101, Iceland.
33
School of Engineering and Natural Sciences, University of Iceland, Reykjavik, 101, Iceland.
34
deCODE genetics/Amgen Inc., Reykjavik, 101, Iceland. kstefans@decode.is.
35
Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland. kstefans@decode.is.

Abstract

Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 × 10-22) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 × 10-13). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR = 1.28, P = 6.6 × 10-10) and aortic root diameter (P = 1.30 × 10-8), and rs1830321 associates with BAV (OR = 1.12, P = 5.3 × 10-3) and coronary artery disease (OR = 1.05, P = 9.3 × 10-5). The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS. We show that several pathways are shared by CAD and AS. Causal analysis suggests that the shared risk factors of Lp(a) and non-high-density lipoprotein cholesterol contribute substantially to the frequent co-occurence of these diseases.

PMID:
29511194
PMCID:
PMC5840367
DOI:
10.1038/s41467-018-03252-6
[Indexed for MEDLINE]
Free PMC Article

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