Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study
(2023) In European Heart Journal 44(21). p.1927-1939- 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. 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... (More)
- 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. © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. (Less)
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- author
- Chen, H.Y. ; Martinsson, A. LU and Thanassoulis, G.
- author collaboration
- organization
- publishing date
- 2023
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Aortic stenosis, Gene expression, Genetic risk score, Genome-wide association study, Mendelian randomization, Phenome-wide association study, Adiposity, Aortic Valve Stenosis, Apolipoproteins, Dyslipidemias, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Inflammation, Mendelian Randomization Analysis, Obesity, Polymorphism, Single Nucleotide, Risk Factors, actin related protein 2, alkaline phosphatase, apolipoprotein B, C reactive protein, calcium, gamma glutamyltransferase, interleukin 6, lipoprotein, lipoprotein A, low density lipoprotein cholesterol, Notch4 receptor, sortilin, triacylglycerol, apolipoprotein, aortic stenosis, aortic valve, area under the curve, Article, body mass, calcification, cohort analysis, coronary artery disease, differential gene expression, dyslipidemia, fasting blood glucose level, gene expression, gene linkage disequilibrium, gene locus, gene ontology, gene set enrichment analysis, genetic risk score, genome-wide association study, human, inflammation, KEGG, lipid metabolism, logistic regression analysis, major clinical study, Mendelian randomization analysis, obesity, pathogenicity, phenome wide association study, phenotype, quality control, receiver operating characteristic, risk factor, single nucleotide polymorphism, smoking, systolic blood pressure, adipose tissue inflammation, aortic valve stenosis, complication, genetic predisposition, genetics, meta analysis, procedures
- in
- European Heart Journal
- volume
- 44
- issue
- 21
- pages
- 13 pages
- publisher
- Oxford University Press
- external identifiers
-
- scopus:85160838840
- pmid:37038246
- ISSN
- 0195-668X
- DOI
- 10.1093/eurheartj/ehad142
- language
- English
- LU publication?
- yes
- id
- 5b40fead-5154-492c-8e40-449f31b7e0e5
- date added to LUP
- 2023-11-14 14:39:08
- date last changed
- 2023-11-15 03:00:02
@article{5b40fead-5154-492c-8e40-449f31b7e0e5,
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. 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. © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.}},
author = {{Chen, H.Y. and Martinsson, A. and Thanassoulis, G.}},
issn = {{0195-668X}},
keywords = {{Aortic stenosis; Gene expression; Genetic risk score; Genome-wide association study; Mendelian randomization; Phenome-wide association study; Adiposity; Aortic Valve Stenosis; Apolipoproteins; Dyslipidemias; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Inflammation; Mendelian Randomization Analysis; Obesity; Polymorphism, Single Nucleotide; Risk Factors; actin related protein 2; alkaline phosphatase; apolipoprotein B; C reactive protein; calcium; gamma glutamyltransferase; interleukin 6; lipoprotein; lipoprotein A; low density lipoprotein cholesterol; Notch4 receptor; sortilin; triacylglycerol; apolipoprotein; aortic stenosis; aortic valve; area under the curve; Article; body mass; calcification; cohort analysis; coronary artery disease; differential gene expression; dyslipidemia; fasting blood glucose level; gene expression; gene linkage disequilibrium; gene locus; gene ontology; gene set enrichment analysis; genetic risk score; genome-wide association study; human; inflammation; KEGG; lipid metabolism; logistic regression analysis; major clinical study; Mendelian randomization analysis; obesity; pathogenicity; phenome wide association study; phenotype; quality control; receiver operating characteristic; risk factor; single nucleotide polymorphism; smoking; systolic blood pressure; adipose tissue inflammation; aortic valve stenosis; complication; genetic predisposition; genetics; meta analysis; procedures}},
language = {{eng}},
number = {{21}},
pages = {{1927--1939}},
publisher = {{Oxford University Press}},
series = {{European Heart Journal}},
title = {{Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study}},
url = {{http://dx.doi.org/10.1093/eurheartj/ehad142}},
doi = {{10.1093/eurheartj/ehad142}},
volume = {{44}},
year = {{2023}},
}