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 H.

AU - Mikkelsen, Susan

AU - Jacobsen, Rikke Louise

AU - Dowsett, Joseph

AU - Pedersen, Ole Birger Vesterager

AU - Erikstrup, Christian

AU - Ostrowski, Sisse R.

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 - Söderberg, Stefan

AU - Stefánsson, Kári

AU - Schott, Jean-Jacques

AU - Rader, Daniel J

AU - Clarke, Robert

AU - Engert, James C

AU - Thanassoulis, George

AU - Therapeutic targets for AoRtic stenosis using GEneTics (TARGET) Consortium

N1 - Publisher Copyright: © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.

PY - 2023

Y1 - 2023

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 - Aortic stenosis

KW - Gene expression

KW - Genetic risk score

KW - Genome-wide association study

KW - Mendelian randomization

KW - Phenome-wide association study

U2 - 10.1093/eurheartj/ehad142

DO - 10.1093/eurheartj/ehad142

M3 - Journal article

C2 - 37038246

AN - SCOPUS:85160838840

VL - 44

SP - 1927

EP - 1939

JO - European Heart Journal

JF - European Heart Journal

SN - 0195-668X

IS - 21

ER -