Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study

Hao Yu Chen; Christian Dina; Aeron M Small; Christian M Shaffer; Rebecca T Levinson; Anna Helgadóttir; Romain Capoulade; Hans Markus Munter; Andreas Martinsson; Benjamin J Cairns; Linea C Trudsø; Mary Hoekstra; Hannah A Burr; Thomas W Marsh; Scott M Damrauer; Line Dufresne; Solena Le Scouarnec; David Messika-Zeitoun; Dilrini K Ranatunga; Rachel A Whitmer; Amélie Bonnefond; Garðar Sveinbjornsson; Ragnar Daníelsen; David O Arnar; Gudmundur Thorgeirsson; Unnur Thorsteinsdottir; Daníel F Gudbjartsson; Hilma Hólm; Jonas Ghouse; Morten Salling Olesen; Alex Hørby Christensen; Susan Mikkelsen; Rikke Louise Jacobsen; Joseph Dowsett; Ole Birger Vesterager Pedersen; Christian Erikstrup; Sisse Rye Ostrowski; Christopher J O'Donnell; Matthew J Budoff; Vilmundur Gudnason; Wendy S Post; Jerome I Rotter; Mark Lathrop; Henning Bundgaard; Bengt Johansson; Johan Ljungberg; Ulf Näslund; Thierry Le Tourneau; J Gustav Smith; Quinn S Wells; James C. Engert; George Thanassoulis; Regeneron Genetics Center

doi:10.1093/eurheartj/ehad142

Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study

Hao Yu Chen
, Christian Dina
, Aeron M Small
, Christian M Shaffer
, Rebecca T Levinson
, Anna Helgadóttir
, Romain Capoulade
, Hans Markus Munter
, Andreas Martinsson
, Benjamin J Cairns
, Linea C Trudsø
, Mary Hoekstra
, Hannah A Burr
, Thomas W Marsh
, Scott M Damrauer
, Line Dufresne
, Solena Le Scouarnec
, David Messika-Zeitoun
, Dilrini K Ranatunga
, Rachel A Whitmer

Amélie Bonnefond, Garðar Sveinbjornsson, Ragnar Daníelsen, David O Arnar, Gudmundur Thorgeirsson, Unnur Thorsteinsdottir, Daníel F Gudbjartsson, Hilma Hólm, Jonas Ghouse, Morten Salling Olesen, Alex Hørby Christensen, Susan Mikkelsen, Rikke Louise Jacobsen, Joseph Dowsett, Ole Birger Vesterager Pedersen, Christian Erikstrup, Sisse Rye Ostrowski, Christopher J O'Donnell, Matthew J Budoff, Vilmundur Gudnason, Wendy S Post, Jerome I Rotter, Mark Lathrop, Henning Bundgaard, Bengt Johansson, Johan Ljungberg, Ulf Näslund, Thierry Le Tourneau, J Gustav Smith, Quinn S Wells, James C. Engert^*, George Thanassoulis^*, Regeneron Genetics Center

^*Corresponding author for this work

Clinical Immunology

Research output: Contribution to journal › Article › Research › peer-review

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.

Original language	English
Pages (from-to)	1927-1939
Number of pages	13
Journal	European heart journal
Volume	44
Issue number	21
Early online date	11 Apr 2023
DOIs	https://doi.org/10.1093/eurheartj/ehad142
Publication status	Published - 1 Jun 2023

Funding

Funders	Funder number
FRQS	11537, 41025, 24281
Novo Nordisk Foundation	NNF17OC0027594
University of Copenhagen	PI Søren Brunak

Keywords

Adiposity/genetics
Aortic Valve Stenosis/genetics
Apolipoproteins/genetics
Dyslipidemias/complications
Genetic Predisposition to Disease
Genome-Wide Association Study/methods
Humans
Inflammation
Mendelian Randomization Analysis
Obesity
Polymorphism, Single Nucleotide/genetics
Risk Factors

Access to Document

10.1093/eurheartj/ehad142

Cite this

Chen, H. Y., Dina, C., Small, A. M., Shaffer, C. M., Levinson, R. T., Helgadóttir, A., Capoulade, R., Munter, H. M., Martinsson, A., Cairns, B. J., Trudsø, L. C., Hoekstra, M., Burr, H. A., Marsh, T. W., Damrauer, S. M., Dufresne, L., Le Scouarnec, S., Messika-Zeitoun, D., Ranatunga, D. K., ... Regeneron Genetics Center (2023). Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study. European heart journal, 44(21), 1927-1939. https://doi.org/10.1093/eurheartj/ehad142

@article{2ce44e00e02345e09c3aafe443cdd7f2,

title = "Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study",

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.",

keywords = "Adiposity/genetics, Aortic Valve Stenosis/genetics, Apolipoproteins/genetics, Dyslipidemias/complications, Genetic Predisposition to Disease, Genome-Wide Association Study/methods, Humans, Inflammation, Mendelian Randomization Analysis, Obesity, Polymorphism, Single Nucleotide/genetics, Risk Factors",

author = "Chen, \{Hao Yu\} and Christian Dina and Small, \{Aeron M\} and Shaffer, \{Christian M\} and Levinson, \{Rebecca T\} and Anna Helgad{\'o}ttir and Romain Capoulade and Munter, \{Hans Markus\} and Andreas Martinsson and Cairns, \{Benjamin J\} and Truds{\o}, \{Linea C\} and Mary Hoekstra and Burr, \{Hannah A\} and Marsh, \{Thomas W\} and Damrauer, \{Scott M\} and Line Dufresne and \{Le Scouarnec\}, Solena and David Messika-Zeitoun and Ranatunga, \{Dilrini K\} and Whitmer, \{Rachel A\} and Am{\'e}lie Bonnefond and Gar{\dh}ar Sveinbjornsson and Ragnar Dan{\'i}elsen and Arnar, \{David O\} and Gudmundur Thorgeirsson and Unnur Thorsteinsdottir and Gudbjartsson, \{Dan{\'i}el F\} and Hilma H{\'o}lm and Jonas Ghouse and Olesen, \{Morten Salling\} and Christensen, \{Alex H{\o}rby\} and Susan Mikkelsen and Jacobsen, \{Rikke Louise\} and Joseph Dowsett and Pedersen, \{Ole Birger Vesterager\} and Christian Erikstrup and Ostrowski, \{Sisse Rye\} and O'Donnell, \{Christopher J\} and Budoff, \{Matthew J\} and Vilmundur Gudnason and Post, \{Wendy S\} and Rotter, \{Jerome I\} and Mark Lathrop and Henning Bundgaard and Bengt Johansson and Johan Ljungberg and Ulf N{\"a}slund and \{Le Tourneau\}, Thierry and Smith, \{J Gustav\} and Wells, \{Quinn S\} and Engert, \{James C.\} and George Thanassoulis and \{Regeneron Genetics Center\}",

note = "{\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.",

year = "2023",

month = jun,

day = "1",

doi = "10.1093/eurheartj/ehad142",

language = "English",

volume = "44",

pages = "1927--1939",

journal = "European heart journal",

issn = "0195-668X",

publisher = "Oxford University Press",

number = "21",

}

Chen, HY, Dina, C, Small, AM, Shaffer, CM, Levinson, RT, Helgadóttir, A, Capoulade, R, Munter, HM, Martinsson, A, Cairns, BJ, Trudsø, LC, Hoekstra, M, Burr, HA, Marsh, TW, Damrauer, SM, Dufresne, L, Le Scouarnec, S, Messika-Zeitoun, D, Ranatunga, DK, Whitmer, RA, Bonnefond, A, Sveinbjornsson, G, Daníelsen, R, Arnar, DO, Thorgeirsson, G, Thorsteinsdottir, U, Gudbjartsson, DF, Hólm, H, Ghouse, J, Olesen, MS, Christensen, AH, Mikkelsen, S, Jacobsen, RL, Dowsett, J, Pedersen, OBV, Erikstrup, C, Ostrowski, SR, O'Donnell, CJ, Budoff, MJ, Gudnason, V, Post, WS, Rotter, JI, Lathrop, M, Bundgaard, H, Johansson, B, Ljungberg, J, Näslund, U, Le Tourneau, T, Smith, JG, Wells, QS, Engert, JC, Thanassoulis, G & Regeneron Genetics Center 2023, 'Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study', European heart journal, vol. 44, no. 21, pp. 1927-1939. https://doi.org/10.1093/eurheartj/ehad142

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

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 -

Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study

Abstract

Funding

Keywords

Access to Document

Fingerprint

Cite this