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 Kastrati & 9 others Peter S. Braund, Colin N. A. Palmer, Amparo Aracil, Oliver Husser, Wolfgang Koenig, Heribert Schunkert, Chim C. Lang, Christian Hengstenberg, Nilesh J. Samani

Research output: Contribution to journalArticle

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

Fingerprint

Aortic Valve Stenosis
Coronary Artery Disease
Alleles
Meta-Analysis

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

Cite this

Trenkwalder, Teresa ; Nelson, Christopher P. ; Musameh, Muntaser D. ; Mordi, Ify R. ; Kessler, Thorsten ; Pellegrini, Costanza ; Debiec, Radoslaw ; Rheude, Tobias ; Lazovic, Viktor ; Zeng, Lingyao ; Martinsson, Andreas ; Gustav Smith, J. ; Gådin, Jesper R. ; Franco-Cereceda, Anders ; Eriksson, Per ; Nielsen, Jonas B. ; Graham, Sarah E. ; Willer, Cristen J. ; Hveem, Kristian ; Kastrati, Adnan ; Braund, Peter S. ; Palmer, Colin N. A. ; Aracil, Amparo ; Husser, Oliver ; Koenig, Wolfgang ; Schunkert, Heribert ; Lang, Chim C. ; Hengstenberg, Christian ; Samani, Nilesh J. / Effects of the coronary artery disease associated LPA and 9p21 loci on risk of aortic valve stenosis. In: International journal of cardiology. 2019 ; Vol. 276. pp. 212-217.
@article{9ec4d2fef7074845a86967fddfc85317,
title = "Effects of the coronary artery disease associated LPA and 9p21 loci on risk of aortic valve stenosis",
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.",
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",
author = "Teresa Trenkwalder and Nelson, {Christopher P.} and Musameh, {Muntaser D.} and Mordi, {Ify R.} and Thorsten Kessler and Costanza Pellegrini and Radoslaw Debiec and Tobias Rheude and Viktor Lazovic and Lingyao Zeng and Andreas Martinsson and {Gustav Smith}, J. and G{\aa}din, {Jesper R.} and Anders Franco-Cereceda and Per Eriksson and Nielsen, {Jonas B.} and Graham, {Sarah E.} and Willer, {Cristen J.} and Kristian Hveem and Adnan Kastrati and Braund, {Peter S.} and Palmer, {Colin N. A.} and Amparo Aracil and Oliver Husser and Wolfgang Koenig and Heribert Schunkert and Lang, {Chim C.} and Christian Hengstenberg and Samani, {Nilesh J.}",
note = "Collection and genotyping of the GeneCAST Leicester cohorts were supported by the Leicester NIHR Biomedical Centre. NJS and CPN are funded by the British Heart Foundation and NJS is a NIHR Senior Investigator. IRM is supported by a NHS Education for Scotland/Chief Scientist Office Postdoctoral Clinical Lectureship [grant number: PCL17/07]. CCL acknowledges support from the British Heart Foundation [grant numbers: PG/16/32/32132 and PG/14/4/30539]. JGS was supported by the European Research Council, Swedish Heart-Lung Foundation, the Wallenberg Center for Molecular Medicine at Lund University, the Swedish Research Council, the Crafoord Foundation, governmental funding of clinical research within the Swedish National Health Service, Sk{\aa}ne University Hospital in Lund, and the Scania county.",
year = "2019",
month = "2",
day = "1",
doi = "10.1016/j.ijcard.2018.11.094",
language = "English",
volume = "276",
pages = "212--217",
journal = "International journal of cardiology",
issn = "0167-5273",
publisher = "Elsevier",

}

Trenkwalder, T, Nelson, CP, Musameh, MD, Mordi, IR, Kessler, T, Pellegrini, C, Debiec, R, Rheude, T, Lazovic, V, Zeng, L, Martinsson, A, Gustav Smith, J, Gådin, JR, Franco-Cereceda, A, Eriksson, P, Nielsen, JB, Graham, SE, Willer, CJ, Hveem, K, Kastrati, A, Braund, PS, Palmer, CNA, Aracil, A, Husser, O, Koenig, W, Schunkert, H, Lang, CC, Hengstenberg, C & Samani, NJ 2019, 'Effects of the coronary artery disease associated LPA and 9p21 loci on risk of aortic valve stenosis', International journal of cardiology, vol. 276, pp. 212-217. https://doi.org/10.1016/j.ijcard.2018.11.094

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; Zeng, Lingyao; Martinsson, Andreas; Gustav Smith, J.; Gådin, Jesper R.; Franco-Cereceda, Anders; Eriksson, Per; Nielsen, Jonas B.; Graham, Sarah E.; Willer, Cristen J.; Hveem, Kristian; Kastrati, Adnan; Braund, Peter S.; Palmer, Colin N. A.; Aracil, Amparo; Husser, Oliver; Koenig, Wolfgang; Schunkert, Heribert; Lang, Chim C. (Lead / Corresponding author); Hengstenberg, Christian (Lead / Corresponding author); Samani, Nilesh J. (Lead / Corresponding author).

In: International journal of cardiology, Vol. 276, 01.02.2019, p. 212-217.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Effects of the coronary artery disease associated LPA and 9p21 loci on risk of aortic valve stenosis

AU - Trenkwalder, Teresa

AU - Nelson, Christopher P.

AU - Musameh, Muntaser D.

AU - Mordi, Ify R.

AU - Kessler, Thorsten

AU - Pellegrini, Costanza

AU - Debiec, Radoslaw

AU - Rheude, Tobias

AU - Lazovic, Viktor

AU - Zeng, Lingyao

AU - Martinsson, Andreas

AU - Gustav Smith, J.

AU - Gådin, Jesper R.

AU - Franco-Cereceda, Anders

AU - Eriksson, Per

AU - Nielsen, Jonas B.

AU - Graham, Sarah E.

AU - Willer, Cristen J.

AU - Hveem, Kristian

AU - Kastrati, Adnan

AU - Braund, Peter S.

AU - Palmer, Colin N. A.

AU - Aracil, Amparo

AU - Husser, Oliver

AU - Koenig, Wolfgang

AU - Schunkert, Heribert

AU - Lang, Chim C.

AU - Hengstenberg, Christian

AU - Samani, Nilesh J.

N1 - Collection and genotyping of the GeneCAST Leicester cohorts were supported by the Leicester NIHR Biomedical Centre. NJS and CPN are funded by the British Heart Foundation and NJS is a NIHR Senior Investigator. IRM is supported by a NHS Education for Scotland/Chief Scientist Office Postdoctoral Clinical Lectureship [grant number: PCL17/07]. CCL acknowledges support from the British Heart Foundation [grant numbers: PG/16/32/32132 and PG/14/4/30539]. JGS was supported by the European Research Council, Swedish Heart-Lung Foundation, the Wallenberg Center for Molecular Medicine at Lund University, the Swedish Research Council, the Crafoord Foundation, governmental funding of clinical research within the Swedish National Health Service, Skåne University Hospital in Lund, and the Scania county.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

KW - 9p21

KW - Aortic valve stenosis

KW - Lipoprotein (a)

KW - Risk factors

KW - Valvular heart disease

KW - Chromosomes, Human, Pair 9/genetics

KW - Humans

KW - Middle Aged

KW - Lipoprotein(a)/genetics

KW - Aortic Valve Stenosis/diagnosis

KW - Genetic Predisposition to Disease/genetics

KW - Male

KW - Genetic Variation/genetics

KW - Case-Control Studies

KW - Coronary Artery Disease/diagnosis

KW - Polymorphism, Single Nucleotide/genetics

KW - Genome-Wide Association Study/methods

KW - Female

KW - Genetic Loci/genetics

KW - Aged

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85057002644&origin=inward&txGid=26d98cd5f80a75d4f2279bdba8d9c2dd

U2 - 10.1016/j.ijcard.2018.11.094

DO - 10.1016/j.ijcard.2018.11.094

M3 - Article

VL - 276

SP - 212

EP - 217

JO - International journal of cardiology

JF - International journal of cardiology

SN - 0167-5273

ER -