TY - JOUR
T1 - Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis
T2 - a genome-wide study
AU - Chen, Hao Yu
AU - Dina, Christian
AU - Small, Aeron M
AU - Shaffer, Christian M
AU - Levinson, Rebecca T
AU - Helgadóttir, Anna
AU - Capoulade, Romain
AU - Munter, Hans Markus
AU - Martinsson, Andreas
AU - Cairns, Benjamin J
AU - Trudsø, Linea C
AU - Hoekstra, Mary
AU - Burr, Hannah A
AU - Marsh, Thomas W
AU - Damrauer, Scott M
AU - Dufresne, Line
AU - Le Scouarnec, Solena
AU - Messika-Zeitoun, David
AU - Ranatunga, Dilrini K
AU - Whitmer, Rachel A
AU - Bonnefond, Amélie
AU - Sveinbjornsson, Garðar
AU - Daníelsen, Ragnar
AU - Arnar, David O
AU - Thorgeirsson, Gudmundur
AU - Thorsteinsdottir, Unnur
AU - Gudbjartsson, Daníel F
AU - Hólm, Hilma
AU - Ghouse, Jonas
AU - Olesen, Morten Salling
AU - Christensen, Alex Hørby
AU - Mikkelsen, Susan
AU - Jacobsen, Rikke Louise
AU - Dowsett, Joseph
AU - Pedersen, Ole Birger Vesterager
AU - Erikstrup, Christian
AU - Ostrowski, Sisse Rye
AU - O'Donnell, Christopher J
AU - Budoff, Matthew J
AU - Gudnason, Vilmundur
AU - Post, Wendy S
AU - Rotter, Jerome I
AU - Lathrop, Mark
AU - Bundgaard, Henning
AU - Johansson, Bengt
AU - Ljungberg, Johan
AU - Näslund, Ulf
AU - Le Tourneau, Thierry
AU - Smith, J Gustav
AU - Wells, Quinn S
AU - Engert, James C.
AU - Thanassoulis, George
AU - Regeneron Genetics Center
N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.
PY - 2023/6/1
Y1 - 2023/6/1
N2 - 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.
AB - 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.
KW - Adiposity/genetics
KW - Aortic Valve Stenosis/genetics
KW - Apolipoproteins/genetics
KW - Dyslipidemias/complications
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study/methods
KW - Humans
KW - Inflammation
KW - Mendelian Randomization Analysis
KW - Obesity
KW - Polymorphism, Single Nucleotide/genetics
KW - Risk Factors
U2 - 10.1093/eurheartj/ehad142
DO - 10.1093/eurheartj/ehad142
M3 - Article
C2 - 37038246
SN - 0195-668X
VL - 44
SP - 1927
EP - 1939
JO - European heart journal
JF - European heart journal
IS - 21
ER -