The effect of LPA Thr3888Pro on lipoprotein(a) and coronary artery disease is modified by the LPA KIV-2 variant 4925G>A.

Apolipoproteins A Coronary Artery Disease / epidemiology Humans Lipoprotein(a) / genetics Polymorphism, Single Nucleotide Risk Factors
Apolipoprotein(a) Coronary artery disease Kringle IV-2 repeat Lipoprotein(a) Mutation SNP interaction

Journal

Atherosclerosis
ISSN: 1879-1484
Titre abrégé: Atherosclerosis
Pays: Ireland
ID NLM: 0242543

Informations de publication

Date de publication:
05 2022
Historique:
received: 21 02 2022
revised: 06 04 2022
accepted: 20 04 2022
pubmed: 10 5 2022
medline: 26 5 2022
entrez: 9 5 2022
Statut: ppublish

Résumé

High lipoprotein(a) [Lp(a)] concentrations are associated with increased coronary artery disease (CAD) risk. Lp(a) is regulated mainly genetically by the LPA gene but involved genetic variants have not been fully elucidated. Improved understanding of the entanglements of genetic Lp(a) regulation may enhance genetic prediction of Lp(a) and CAD risk. We investigated an interaction between the well-known LPA missense SNP rs41272110 (known as Thr3888Pro) and the frequent LPA splicing mutation KIV-2 4925G>A. Effects on Lp(a) concentrations were investigated by multiple quantile regression in the German Chronic Kidney Disease (GCKD) study, KORA-F3 and KORA-F4 (n We observed a significant SNP-SNP interaction in all studies (p = 1.26e-05 to 3.03e-04). In quantile regression analysis, rs41272110 as a predictor shows no impact on Lp(a) (β = -0.06 [-0.79; 0.68], p = 0.879), but in a joint model including both SNPs as predictors, rs41272110 is associated with markedly higher Lp(a) (β = +9.40 mg/dL [6.45; 12.34], p = 4.07e-10). Similarly, rs41272110 shows no effect on CAD in UKB (HR = 1.01 [0.97; 1.04], p = 0.731), while rs41272110 carriers not carrying 4925G>A show an increased CAD risk (HR = 1.10 [1.04; 1.16], p = 6.9e-04). This group corresponds to 4% of the population. Adjustment for apolipoprotein(a) isoforms further modified the effect estimates markedly. This work emphasizes the complexity of the genetic regulation of Lp(a) and the importance to account for genetic subgroups in Lp(a) association studies and when interpreting genetic cardiovascular risk profiles.

Sections du résumé

BACKGROUND AND AIMS
High lipoprotein(a) [Lp(a)] concentrations are associated with increased coronary artery disease (CAD) risk. Lp(a) is regulated mainly genetically by the LPA gene but involved genetic variants have not been fully elucidated. Improved understanding of the entanglements of genetic Lp(a) regulation may enhance genetic prediction of Lp(a) and CAD risk. We investigated an interaction between the well-known LPA missense SNP rs41272110 (known as Thr3888Pro) and the frequent LPA splicing mutation KIV-2 4925G>A.
METHODS
Effects on Lp(a) concentrations were investigated by multiple quantile regression in the German Chronic Kidney Disease (GCKD) study, KORA-F3 and KORA-F4 (n
RESULTS
We observed a significant SNP-SNP interaction in all studies (p = 1.26e-05 to 3.03e-04). In quantile regression analysis, rs41272110 as a predictor shows no impact on Lp(a) (β = -0.06 [-0.79; 0.68], p = 0.879), but in a joint model including both SNPs as predictors, rs41272110 is associated with markedly higher Lp(a) (β = +9.40 mg/dL [6.45; 12.34], p = 4.07e-10). Similarly, rs41272110 shows no effect on CAD in UKB (HR = 1.01 [0.97; 1.04], p = 0.731), while rs41272110 carriers not carrying 4925G>A show an increased CAD risk (HR = 1.10 [1.04; 1.16], p = 6.9e-04). This group corresponds to 4% of the population. Adjustment for apolipoprotein(a) isoforms further modified the effect estimates markedly.
CONCLUSIONS
This work emphasizes the complexity of the genetic regulation of Lp(a) and the importance to account for genetic subgroups in Lp(a) association studies and when interpreting genetic cardiovascular risk profiles.

Identifiants

DOI: 10.1016/j.atherosclerosis.2022.04.023 PMID: 35534298 PMC: PMC7613586
pubmed: 35534298
pii: S0021-9150(22)00213-1
doi: 10.1016/j.atherosclerosis.2022.04.023
pmc: PMC7613586
mid: EMS152739
pii:
doi:

Substances chimiques

Apolipoproteins A 0
Lipoprotein(a) 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

151-159

Subventions

Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : Austrian Science Fund FWF
ID : P 31458
Pays : Austria

Informations de copyright

Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.

Références

Nephrol Dial Transplant. 2015 Mar;30(3):441-51
pubmed: 25271006
Eur Heart J. 2017 Jun 14;38(23):1823-1831
pubmed: 28444229
Nat Genet. 2016 Oct;48(10):1284-1287
pubmed: 27571263
J Med Genet. 2006 Dec;43(12):917-23
pubmed: 16840570
Arterioscler Thromb Vasc Biol. 2021 May 5;41(5):1792-1800
pubmed: 33730874
Circ Cardiovasc Genet. 2010 Feb;3(1):39-46
pubmed: 20160194
Circulation. 2017 Jan 17;135(3):251-263
pubmed: 27831500
Circ Genom Precis Med. 2021 Oct;14(5):e003312
pubmed: 34461734
J Am Coll Cardiol. 2010 May 11;55(19):2160-7
pubmed: 20447543
Nat Genet. 2016 Oct;48(10):1279-83
pubmed: 27548312
Thromb Haemost. 1999 Dec;82(6):1709-17
pubmed: 10613659
J Lipid Res. 1995 Apr;36(4):813-22
pubmed: 7542309
J Lipid Res. 1990 Apr;31(4):603-13
pubmed: 2141054
Cardiovasc Res. 2014 Jul 1;103(1):28-36
pubmed: 24760552
J Intern Med. 2013 Jan;273(1):6-30
pubmed: 22998429
PLoS One. 2011 Jan 24;6(1):e14581
pubmed: 21283670
J Am Soc Nephrol. 2000 Jan;11(1):105-115
pubmed: 10616846
JAMA Cardiol. 2018 Jul 1;3(7):619-627
pubmed: 29926099
J Am Coll Cardiol. 2021 Aug 3;78(5):437-449
pubmed: 34325833
Genome Med. 2020 Aug 21;12(1):74
pubmed: 32825847
J Clin Invest. 1994 Apr;93(4):1481-92
pubmed: 8163653
PLoS One. 2020 Apr 28;15(4):e0232073
pubmed: 32343731
Hum Mol Genet. 1997 Jul;6(7):1099-107
pubmed: 9215681
Genome Biol. 2019 May 20;20(1):97
pubmed: 31104630
Arterioscler Thromb Vasc Biol. 2018 May;38(5):1230-1241
pubmed: 29567679
Circ Genom Precis Med. 2021 Feb;14(1):e003182
pubmed: 33522245
Science. 2021 Sep 24;373(6562):1499-1505
pubmed: 34554798
Circulation. 2020 Jun 2;141(22):1826-1828
pubmed: 32479194
J Clin Invest. 1993 Apr;91(4):1630-6
pubmed: 8473506
Hum Mol Genet. 1998 Feb;7(2):257-64
pubmed: 9425232
Cardiovasc Res. 2022 Mar 16;118(4):1088-1102
pubmed: 33878186
Thromb Haemost. 1997 May;77(5):949-54
pubmed: 9184408
Nephrol Dial Transplant. 2012 Apr;27(4):1454-60
pubmed: 21862458
Arterioscler Thromb. 1992 Oct;12(10):1214-26
pubmed: 1390593
Ann Intern Med. 2009 May 5;150(9):604-12
pubmed: 19414839
Nature. 2018 Oct;562(7726):203-209
pubmed: 30305743
Circ Res. 2018 Feb 2;122(3):433-443
pubmed: 29212778
JAMA Cardiol. 2020 Oct 06;:
pubmed: 33021622
Eur Heart J. 2021 Jun 7;42(22):2186-2196
pubmed: 33709115
Nat Genet. 2018 Sep;50(9):1219-1224
pubmed: 30104762
Gesundheitswesen. 2005 Aug;67 Suppl 1:S26-30
pubmed: 16032514
Atherosclerosis. 2019 Oct;289:201-205
pubmed: 31327478
Hum Mol Genet. 2001 Apr 1;10(8):815-24
pubmed: 11285247
Nucleic Acids Res. 2021 Jan 8;49(D1):D480-D489
pubmed: 33237286
JACC Heart Fail. 2016 Jan;4(1):78-87
pubmed: 26656145
J Lipid Res. 2009 Apr;50(4):768-72
pubmed: 19060253
Clin Chim Acta. 2009 Jul;405(1-2):39-42
pubmed: 19348789
Eur Heart J. 2019 Sep 1;40(33):2760-2770
pubmed: 30608559
J Lipid Res. 2016 Nov;57(11):1953-1975
pubmed: 27677946

Auteurs

Rebecca Grüneis (R)

Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Austria.

Claudia Lamina (C)

Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Austria.

Silvia Di Maio (S)

Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Austria.

Sebastian Schönherr (S)

Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Austria.

Peter Zoescher (P)

Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Austria.

Lukas Forer (L)

Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Austria.

Gertraud Streiter (G)

Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Austria.

Annette Peters (A)

German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.

Christian Gieger (C)

German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Anna Köttgen (A)

Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany and German Chronic Kidney Disease Study, Germany.

Florian Kronenberg (F)

Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Austria.

Stefan Coassin (S)

Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Austria. Electronic address: Stefan.Coassin@i-med.ac.at.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Lipoprotéines › Apolipoprotéines › Apolipoprotéines A › The effect of LPA Thr3888Pro on lipoprotein(a)...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Ischémie myocardique › Maladie coronarienne › Maladie des artères coronaires › The effect of LPA Thr3888Pro on lipoprotein(a)...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The effect of LPA Thr3888Pro on lipoprotein(a)...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Lipoprotéines › Lipoprotéine (a) › The effect of LPA Thr3888Pro on lipoprotein(a)...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › The effect of LPA Thr3888Pro on lipoprotein(a)...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Probabilité › Risque › Facteurs de risque › The effect of LPA Thr3888Pro on lipoprotein(a)...