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

Teresa Trenkwalder, Christopher P. Nelson, Muntaser D. Musameh, Ify R. Mordi, Thorsten Kessler, Costanza Pellegrini, Radoslaw Debiec, Tobias Rheude, Viktor Lazovic, Lingyao Zeng, Andreas Martinsson, J. Gustav Smith, Jesper R. Gådin, Anders Franco-Cereceda, Per Eriksson, Jonas B. Nielsen, Sarah E. Graham, Cristen J. Willer, Kristian Hveem, Adnan KastratiPeter S. Braund, Colin N. A. Palmer, Amparo Aracil, Oliver Husser, Wolfgang Koenig, Heribert Schunkert, Chim C. Lang, Christian Hengstenberg, Nilesh J. Samani

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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 7,880 cases and 851,152 controls.

Results: In the meta-analysis including 4,651 cases and 8,231 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=6.9x10-10) 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.
Original languageEnglish
Pages (from-to)212-217
Number of pages6
JournalInternational Journal of Cardiology
Volume276
Early online date17 Nov 2018
DOIs
Publication statusPublished - 1 Feb 2019

Keywords

  • 9p21
  • Aortic valve stenosis
  • Lipoprotein (a)
  • Risk factors
  • Valvular heart disease
  • Chromosomes, Human, Pair 9/genetics
  • Humans
  • Middle Aged
  • Lipoprotein(a)/genetics
  • Aortic Valve Stenosis/diagnosis
  • Genetic Predisposition to Disease/genetics
  • Male
  • Genetic Variation/genetics
  • Case-Control Studies
  • Coronary Artery Disease/diagnosis
  • Polymorphism, Single Nucleotide/genetics
  • Genome-Wide Association Study/methods
  • Female
  • Genetic Loci/genetics
  • Aged

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    Trenkwalder, T., Nelson, C. P., Musameh, M. D., Mordi, I. R., Kessler, T., Pellegrini, C., Debiec, R., Rheude, T., Lazovic, V., Zeng, L., Martinsson, A., Gustav Smith, J., Gådin, J. R., Franco-Cereceda, A., Eriksson, P., Nielsen, J. B., Graham, S. E., Willer, C. J., Hveem, K., ... Samani, N. J. (2019). Effects of the coronary artery disease associated LPA and 9p21 loci on risk of aortic valve stenosis. International Journal of Cardiology, 276, 212-217. https://doi.org/10.1016/j.ijcard.2018.11.094