| Title: | Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study |
| Journal: | European Heart Journal |
| Published: | 11 Apr 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37038246/ |
| DOI: | https://doi.org/10.1093/eurheartj/ehad142 |
| URL: | https://academic.oup.com/eurheartj/advance-article-pdf/doi/10.1093/eurheartj/ehad142/49811307/ehad142.pdf |
Publication 11323
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Abstract
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.</p>
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.</p>
CONCLUSION: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.</p>
58 Authors
- Hao Yu Chen
- Christian Dina
- Aeron M Small
- Christian M Shaffer
- Rebecca T Levinson
- Anna Helgadóttir
- Romain Capoulade
- Hans Markus Munter
- Andreas Martinsson
- Benjamin J Cairns
- Linea C Trudsø
- Mary Hoekstra
- Hannah A Burr
- Thomas W Marsh
- Scott M Damrauer
- Line Dufresne
- Solena Le Scouarnec
- David Messika-Zeitoun
- Dilrini K Ranatunga
- Rachel A Whitmer
- Amélie Bonnefond
- Garðar Sveinbjornsson
- Ragnar Daníelsen
- David O Arnar
- Gudmundur Thorgeirsson
- Unnur Thorsteinsdottir
- Daníel F Gudbjartsson
- Hilma Hólm
- Jonas Ghouse
- Morten Salling Olesen
- Alex H Christensen
- Susan Mikkelsen
- Rikke Louise Jacobsen
- Joseph Dowsett
- Ole Birger Vesterager Pedersen
- Christian Erikstrup
- Sisse R Ostrowski
- Regeneron Genetics Center
- Christopher J O'Donnell
- Matthew J Budoff
- Vilmundur Gudnason
- Wendy S Post
- Jerome I Rotter
- Mark Lathrop
- Henning Bundgaard
- Bengt Johansson
- Johan Ljungberg
- Ulf Näslund
- Thierry Le Tourneau
- J Gustav Smith
- Quinn S Wells
- Stefan Söderberg
- Kári Stefánsson
- Jean-Jacques Schott
- Daniel J Rader
- Robert Clarke
- James C Engert
- George Thanassoulis
3 Applications
| Application ID | Title |
|---|---|
| 11537 | Epidemiology of aortic stenosis |
| 24281 | Identifying genetic determinants of coronary heart disease in individuals with diabetes |
| 41025 | Pleiotropic effects of cardiometabolic genetic markers and their interaction with diet and fatty acids in cardiovascular diseases. |
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