A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms

Salome Mack, Stefan Coassin, Rico Rueedi, Noha Yousri, Ilkka Seppälä, Christian Gieger, Sebastian Schönherr, Lukas Forer, Gertraud Erhart, Pedro Marques-Vidal, Janina S. Ried, Gerard Waeber, Sven Bergmann, Doreen Dähnhardt, Andrea Stöckl, Olli T. Raitakari, Mika Kähönen, Annette Peters, Thomas Meitinger, Konstantin StrauchLudmilla Kedenko, Bernhard Paulweber, Terho Lehtimäki, Steven Hunt, Peter Vollenweider, Claudia Lamina, Florian Kronenberg

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from fve genome-wide association studies (n = 13,781). We identifed 48 independent SNPs in the LPA and 1 SNP in the APOE gene region to be signifcantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the LPA, 1 in the APOE gene region). Seven SNPs showed a genome-wide signifcant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, P = 3.35 × 10-30). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the APOE2-determining allele of rs7412 to be signifcantly associated with Lp(a) concentrations (P = 3.47 × 10-10). Each APOE2 allele decreased Lp(a) by 3.34 mg/dl corresponding to 15% of the population's mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one signifcant association of the TLR2 gene with Lp(a) (P = 3.4 × 10fl4). In summary, we identifed a large number of independent SNPs in the LPA gene region, as well as the APOE2 allele, to be signifcantly associated with Lp(a) concentrations.

Original languageEnglish
Pages (from-to)1834-1844
Number of pages11
JournalJournal of Lipid Research
Volume58
Issue number9
DOIs
Publication statusPublished - 1 Jan 2017

Fingerprint

Apoprotein(a)
Lipoprotein(a)
Genome-Wide Association Study
Meta-Analysis
Protein Isoforms
Genes
Single Nucleotide Polymorphism
Alleles
Coronary Artery Disease
Kringles
Genetic Loci

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms. / Mack, Salome; Coassin, Stefan; Rueedi, Rico; Yousri, Noha; Seppälä, Ilkka; Gieger, Christian; Schönherr, Sebastian; Forer, Lukas; Erhart, Gertraud; Marques-Vidal, Pedro; Ried, Janina S.; Waeber, Gerard; Bergmann, Sven; Dähnhardt, Doreen; Stöckl, Andrea; Raitakari, Olli T.; Kähönen, Mika; Peters, Annette; Meitinger, Thomas; Strauch, Konstantin; Kedenko, Ludmilla; Paulweber, Bernhard; Lehtimäki, Terho; Hunt, Steven; Vollenweider, Peter; Lamina, Claudia; Kronenberg, Florian.

In: Journal of Lipid Research, Vol. 58, No. 9, 01.01.2017, p. 1834-1844.

Research output: Contribution to journalArticle

Mack, S, Coassin, S, Rueedi, R, Yousri, N, Seppälä, I, Gieger, C, Schönherr, S, Forer, L, Erhart, G, Marques-Vidal, P, Ried, JS, Waeber, G, Bergmann, S, Dähnhardt, D, Stöckl, A, Raitakari, OT, Kähönen, M, Peters, A, Meitinger, T, Strauch, K, Kedenko, L, Paulweber, B, Lehtimäki, T, Hunt, S, Vollenweider, P, Lamina, C & Kronenberg, F 2017, 'A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms', Journal of Lipid Research, vol. 58, no. 9, pp. 1834-1844. https://doi.org/10.1194/jlr.M076232
Mack, Salome ; Coassin, Stefan ; Rueedi, Rico ; Yousri, Noha ; Seppälä, Ilkka ; Gieger, Christian ; Schönherr, Sebastian ; Forer, Lukas ; Erhart, Gertraud ; Marques-Vidal, Pedro ; Ried, Janina S. ; Waeber, Gerard ; Bergmann, Sven ; Dähnhardt, Doreen ; Stöckl, Andrea ; Raitakari, Olli T. ; Kähönen, Mika ; Peters, Annette ; Meitinger, Thomas ; Strauch, Konstantin ; Kedenko, Ludmilla ; Paulweber, Bernhard ; Lehtimäki, Terho ; Hunt, Steven ; Vollenweider, Peter ; Lamina, Claudia ; Kronenberg, Florian. / A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms. In: Journal of Lipid Research. 2017 ; Vol. 58, No. 9. pp. 1834-1844.
@article{a2fa8ca66189425a9c3ff1b1287aa279,
title = "A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms",
abstract = "High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from fve genome-wide association studies (n = 13,781). We identifed 48 independent SNPs in the LPA and 1 SNP in the APOE gene region to be signifcantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the LPA, 1 in the APOE gene region). Seven SNPs showed a genome-wide signifcant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1{\%}) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, P = 3.35 × 10-30). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the APOE2-determining allele of rs7412 to be signifcantly associated with Lp(a) concentrations (P = 3.47 × 10-10). Each APOE2 allele decreased Lp(a) by 3.34 mg/dl corresponding to 15{\%} of the population's mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one signifcant association of the TLR2 gene with Lp(a) (P = 3.4 × 10fl4). In summary, we identifed a large number of independent SNPs in the LPA gene region, as well as the APOE2 allele, to be signifcantly associated with Lp(a) concentrations.",
author = "Salome Mack and Stefan Coassin and Rico Rueedi and Noha Yousri and Ilkka Sepp{\"a}l{\"a} and Christian Gieger and Sebastian Sch{\"o}nherr and Lukas Forer and Gertraud Erhart and Pedro Marques-Vidal and Ried, {Janina S.} and Gerard Waeber and Sven Bergmann and Doreen D{\"a}hnhardt and Andrea St{\"o}ckl and Raitakari, {Olli T.} and Mika K{\"a}h{\"o}nen and Annette Peters and Thomas Meitinger and Konstantin Strauch and Ludmilla Kedenko and Bernhard Paulweber and Terho Lehtim{\"a}ki and Steven Hunt and Peter Vollenweider and Claudia Lamina and Florian Kronenberg",
year = "2017",
month = "1",
day = "1",
doi = "10.1194/jlr.M076232",
language = "English",
volume = "58",
pages = "1834--1844",
journal = "Journal of Lipid Research",
issn = "0022-2275",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "9",

}

TY - JOUR

T1 - A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms

AU - Mack, Salome

AU - Coassin, Stefan

AU - Rueedi, Rico

AU - Yousri, Noha

AU - Seppälä, Ilkka

AU - Gieger, Christian

AU - Schönherr, Sebastian

AU - Forer, Lukas

AU - Erhart, Gertraud

AU - Marques-Vidal, Pedro

AU - Ried, Janina S.

AU - Waeber, Gerard

AU - Bergmann, Sven

AU - Dähnhardt, Doreen

AU - Stöckl, Andrea

AU - Raitakari, Olli T.

AU - Kähönen, Mika

AU - Peters, Annette

AU - Meitinger, Thomas

AU - Strauch, Konstantin

AU - Kedenko, Ludmilla

AU - Paulweber, Bernhard

AU - Lehtimäki, Terho

AU - Hunt, Steven

AU - Vollenweider, Peter

AU - Lamina, Claudia

AU - Kronenberg, Florian

PY - 2017/1/1

Y1 - 2017/1/1

N2 - High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from fve genome-wide association studies (n = 13,781). We identifed 48 independent SNPs in the LPA and 1 SNP in the APOE gene region to be signifcantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the LPA, 1 in the APOE gene region). Seven SNPs showed a genome-wide signifcant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, P = 3.35 × 10-30). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the APOE2-determining allele of rs7412 to be signifcantly associated with Lp(a) concentrations (P = 3.47 × 10-10). Each APOE2 allele decreased Lp(a) by 3.34 mg/dl corresponding to 15% of the population's mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one signifcant association of the TLR2 gene with Lp(a) (P = 3.4 × 10fl4). In summary, we identifed a large number of independent SNPs in the LPA gene region, as well as the APOE2 allele, to be signifcantly associated with Lp(a) concentrations.

AB - High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from fve genome-wide association studies (n = 13,781). We identifed 48 independent SNPs in the LPA and 1 SNP in the APOE gene region to be signifcantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the LPA, 1 in the APOE gene region). Seven SNPs showed a genome-wide signifcant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, P = 3.35 × 10-30). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the APOE2-determining allele of rs7412 to be signifcantly associated with Lp(a) concentrations (P = 3.47 × 10-10). Each APOE2 allele decreased Lp(a) by 3.34 mg/dl corresponding to 15% of the population's mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one signifcant association of the TLR2 gene with Lp(a) (P = 3.4 × 10fl4). In summary, we identifed a large number of independent SNPs in the LPA gene region, as well as the APOE2 allele, to be signifcantly associated with Lp(a) concentrations.

UR - http://www.scopus.com/inward/record.url?scp=85029424122&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029424122&partnerID=8YFLogxK

U2 - 10.1194/jlr.M076232

DO - 10.1194/jlr.M076232

M3 - Article

C2 - 28512139

AN - SCOPUS:85029424122

VL - 58

SP - 1834

EP - 1844

JO - Journal of Lipid Research

JF - Journal of Lipid Research

SN - 0022-2275

IS - 9

ER -