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

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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.

Detaljer

Författare
  • Teresa Trenkwalder
  • Christopher P. Nelson
  • Muntaser D. Musameh
  • Ify R. Mordi
  • Thorsten Kessler
  • Costanza Pellegrini
  • Radoslaw Debiec
  • Tobias Rheude
  • Viktor Lazovic
  • Lingyao Zeng
  • Jesper R. Gådin
  • Anders Franco-Cereceda
  • Per Eriksson
  • Jonas B. Nielsen
  • Sarah E. Graham
  • Cristen J. Willer
  • Kristian Hveem
  • Adnan Kastrati
  • Peter S. Braund
  • Colin N.A. Palmer
  • Amparo Aracil
  • Oliver Husser
  • Wolfgang Koenig
  • Heribert Schunkert
  • Chim C. Lang
  • Christian Hengstenberg
  • Nilesh J. Samani
Enheter & grupper
Externa organisationer
  • Technical University of Munich
  • University of Leicester
  • University of Dundee
  • Sahlgrenska University Hospital
  • Karolinska University Hospital
  • University of Michigan
  • Norwegian University of Science and Technology
  • German Centre for Cardiovascular Research
  • St.-Johannes-Hospital Dortmund
  • Medical University of Vienna
  • Ninewells Hospital and Medical School
  • Skåne University Hospital
  • Karolinska Institute
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Kardiologi
  • Medicinsk genetik

Nyckelord

Originalspråkengelska
Sidor (från-till)212-217
TidskriftInternational Journal of Cardiology
Volym276
Tidigt onlinedatum2018 nov 17
StatusPublished - 2019 feb
PublikationskategoriForskning
Peer review utfördJa