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Distinct Genetic Risk Profile Found in Aortic Stenosis
Quick Takes
- There was a genetic distinction identified among development of aortic stenosis (AS) and elevated serum phosphate levels contributed to risk.
- The genetic correlation among coronary artery disease and AS was only found to be moderate.
Study Questions:
Which genetic and cardiovascular risk factors are aortic stenosis (AS)-specific, and which could be shared between AS and with coronary artery disease (CAD)?
Methods:
Researchers performed a genomewide association study (GWAS) meta-analysis, which included a total of 18,792 participants with AS and 434,249 control participants, all of European ancestry. This was performed using eight individual European AS GWAS and participants were recruited through the European Consortium for Genetics of Aortic Stenosis. CAD was identified by medical history, International Classification of Diseases (ICD)-9/10 codes, or coronary angiograms. Exclusions included known bicuspid aortic valves. Biological processes were identified that were enriched specifically in genes associated with AS, while being absent in CAD-associated genes. Tissues involved in adiposity, metabolism, inflammation, or calcification were identified, which may contribute to AS development. A follow-up analysis on cardiovascular traits and tissue transcriptome data were also performed using the GWAS data.
Results:
Of the 18,792 participants with AS and 434,249 control participants, there were 17 AS risk loci, including 5 loci with novel and independently replicated associations (RNF114A, AFAP1, PDGFRA, ADAMTS7, HAO1). From the 17 associated loci, 11 were associated with risk specifically for AS and were not associated with CAD (ALPL, PALMD, PRRX1, RNF144A, MECOM, AFAP1, PDGFRA, IL6, TPCN2, NLRP6, HAO1). A moderate genetic correlation of 0.15 (standard error, 0.05) between AS and CAD (p = 1.60 × 10−3) was identified. Mendelian randomization revealed that serum phosphate was an AS-specific risk factor that was not identified in CAD (AS: odds ratio [OR], 1.20; 95% confidence interval [CI], 1.11-1.31; p = 1.27 × 10−5; CAD: OR, 0.97; 95% CI, 0.94-1.00; p = 0.04). Additionally, the analysis revealed a weaker association between AS and factors such as blood pressure, body mass index, and cholesterol metabolism, compared to CAD.
Conclusions:
Despite sharing similar features such as inflammation, smooth muscle cell proliferation, and calcification, the genetic association among AS and CAD was found to be moderate. Cardiovascular disease risk factors such as elevated blood pressure and increased lipids show a weaker correlation to AS compared to CAD. For AS, increased serum phosphate levels were a determined risk factor. The GWAS analysis identified 17 AS risk loci and corresponding candidate genes and found that most AS risk loci were independent of CAD. Out of the 17 risk loci, 11 of these showed no association with CAD. This research determined that there are multiple biological pathways and patterns of gene expression in different tissue, which contributes to AS risk.
Perspective:
Increasing our understanding of AS development at the genetic level can inform future research and treatment options. This research complements previous studies by confirming that AS and CAD not only have different genetic risks, but their targets for treatment may be quite different. By continuing to investigate causes of AS and CAD, we can turn our focus to novel therapies to treat these burdensome and deadly disease states.
Clinical Topics: Arrhythmias and Clinical EP, Valvular Heart Disease, Atherosclerotic Disease (CAD/PAD), Genetic Arrhythmic Conditions, Cardiovascular Care Team, Prevention
Keywords: Aortic Valve Stenosis, Coronary Artery Disease, Genetics, Risk
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