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

Trenkwalder, Teresa; Nelson, Christopher P.; Musameh, Muntaser D.; Mordi, Ify R.; Kessler, Thorsten; Pellegrini, Costanza; Debiec, Radoslaw; Rheude, Tobias; Lazovic, Viktor and Zeng, Lingyao, et al. (2019) In International Journal of Cardiology 276. p.212-217
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... (More)

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.

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@article{47cbd882-7e45-480e-805e-76835ed47fa6,
  abstract     = {<p>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<sup>−10</sup>) 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.</p>},
  author       = {Trenkwalder, Teresa and Nelson, Christopher P. and Musameh, Muntaser D. and Mordi, Ify R. and Kessler, Thorsten and Pellegrini, Costanza and Debiec, Radoslaw and Rheude, Tobias and Lazovic, Viktor and Zeng, Lingyao and Martinsson, Andreas and Gustav Smith, J. and Gådin, Jesper R. and Franco-Cereceda, Anders and Eriksson, Per and Nielsen, Jonas B. and Graham, Sarah E. and Willer, Cristen J. and Hveem, Kristian and Kastrati, Adnan and Braund, Peter S. and Palmer, Colin N.A. and Aracil, Amparo and Husser, Oliver and Koenig, Wolfgang and Schunkert, Heribert and Lang, Chim C. and Hengstenberg, Christian and Samani, Nilesh J.},
  issn         = {0167-5273},
  keyword      = {9p21,Aortic valve stenosis,Lipoprotein (a),Risk factors,Valvular heart disease},
  language     = {eng},
  pages        = {212--217},
  publisher    = {Elsevier},
  series       = {International Journal of Cardiology},
  title        = {Effects of the coronary artery disease associated LPA and 9p21 loci on risk of aortic valve stenosis},
  url          = {http://dx.doi.org/10.1016/j.ijcard.2018.11.094},
  volume       = {276},
  year         = {2019},
}