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Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study
- Source :
- European heart journal, vol 44, iss 21
- Publication Year :
- 2023
- Publisher :
- eScholarship, University of California, 2023.
-
Abstract
- AimsAlthough 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 resultsA 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.ConclusionDyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.
- Subjects :
- Genome-wide association study
Phenome-wide association study
Clinical Sciences
Cardiorespiratory Medicine and Haematology
Cardiovascular
Risk Factors
Mendelian randomization
Genetics
Humans
2.1 Biological and endogenous factors
Genetic Predisposition to Disease
Obesity
Polymorphism
Aetiology
Adiposity
Dyslipidemias
Inflammation
Aortic stenosis
Prevention
Human Genome
Aortic Valve Stenosis
Single Nucleotide
Mendelian Randomization Analysis
Regeneron Genetics Center
Genetic risk score
Apolipoproteins
Heart Disease
Cardiovascular System & Hematology
Gene expression
Genome-Wide Association Study
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- European heart journal, vol 44, iss 21
- Accession number :
- edsair.od.......325..347f0cbc2b57483ad0dd0ce10f254a09