Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study

Research output: Contribution to journalJournal articleResearchpeer-review


  • Fulltext

    Final published version, 8.89 MB, PDF document

  • Quinn S Wells
  • Stefan Söderberg
  • Kári Stefánsson
  • Jean-Jacques Schott
  • Daniel J Rader
  • Robert Clarke
  • James C Engert
  • George Thanassoulis
  • Therapeutic targets for AoRtic stenosis using GEneTics (TARGET) Consortium

Aims Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. Methods and results A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10−8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2–SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26–1.35; P = 2.7 × 10−51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08–1.37; P = 1.4 × 10−3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90–5.12; P = 2.1 × 10−20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17–1.23; P = 4.8 × 10−73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05–1.9; P = 1.9 × 10−12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. Conclusion Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.

Original languageEnglish
JournalEuropean Heart Journal
Issue number21
Pages (from-to)1927-1939
Number of pages13
Publication statusPublished - 2023

Bibliographical note

Publisher Copyright:
© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.

    Research areas

  • Aortic stenosis, Gene expression, Genetic risk score, Genome-wide association study, Mendelian randomization, Phenome-wide association study

ID: 366766981