Genome-Wide Characterization of a Highly Penetrant Form of Hyperlipoprotein(a)emia Associated With Genetically Elevated Cardiovascular Risk.
apolipoproteins
coronary artery disease
lipids
lipoprotein(a)
risk factors
Journal
Circulation. Genomic and precision medicine
ISSN: 2574-8300
Titre abrégé: Circ Genom Precis Med
Pays: United States
ID NLM: 101714113
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
pubmed:
9
2
2022
medline:
22
4
2022
entrez:
8
2
2022
Statut:
ppublish
Résumé
Lp(a) (lipoprotein [a]) is a highly atherogenic lipoprotein strongly associated with coronary artery disease (CAD). Lp(a) concentrations are chiefly determined genetically. Investigation of large pedigrees with extreme Lp(a) using modern whole-genome approaches may unravel the genetic determinants underpinning this pathological phenotype. A large family characterized by high Lp(a) and increased CAD incidence was recruited by cascade screening. Plasma lipids, lipoproteins, and apolipoproteins concentrations, as well as the size of apo(a) isoforms, were determined enzymatically by high-resolution mass spectrometry and Western blot, respectively. Whole-exome sequencing was performed to search for rare defects in modifier genes. Genetic risk scores (GRS) for Lp(a) and CAD were calculated and their discriminative power was assessed. Seventeen individuals displayed extreme Lp(a) levels including 6 with CAD. Whole-exome sequencing showed no hint for genetic defects outside the High-Lp(a) phenotypes can be successfully captured using the Lp(a) GRS even among closely related family members. In hyper-Lp(a) individuals,
Sections du résumé
BACKGROUND
Lp(a) (lipoprotein [a]) is a highly atherogenic lipoprotein strongly associated with coronary artery disease (CAD). Lp(a) concentrations are chiefly determined genetically. Investigation of large pedigrees with extreme Lp(a) using modern whole-genome approaches may unravel the genetic determinants underpinning this pathological phenotype.
METHODS
A large family characterized by high Lp(a) and increased CAD incidence was recruited by cascade screening. Plasma lipids, lipoproteins, and apolipoproteins concentrations, as well as the size of apo(a) isoforms, were determined enzymatically by high-resolution mass spectrometry and Western blot, respectively. Whole-exome sequencing was performed to search for rare defects in modifier genes. Genetic risk scores (GRS) for Lp(a) and CAD were calculated and their discriminative power was assessed.
RESULTS
Seventeen individuals displayed extreme Lp(a) levels including 6 with CAD. Whole-exome sequencing showed no hint for genetic defects outside the
CONCLUSIONS
High-Lp(a) phenotypes can be successfully captured using the Lp(a) GRS even among closely related family members. In hyper-Lp(a) individuals,
Identifiants
pubmed: 35133173
doi: 10.1161/CIRCGEN.121.003489
pmc: PMC9018215
doi:
Substances chimiques
Lipoprotein(a)
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e003489Subventions
Organisme : Austrian Science Fund FWF
ID : P 31458
Pays : Austria
Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Références
Eur Heart J Case Rep. 2019 Feb 25;3(1):ytz019
pubmed: 31020261
Arterioscler Thromb Vasc Biol. 2012 Jul;32(7):1732-41
pubmed: 22516069
Eur Heart J. 2017 Jun 14;38(23):1823-1831
pubmed: 28444229
Science. 2008 Feb 22;319(5866):1100-4
pubmed: 18292342
Clin Chim Acta. 1987 Apr 15;164(1):93-100
pubmed: 2953508
J Lipid Res. 2018 May;59(5):892-900
pubmed: 29540575
Circ Cardiovasc Genet. 2016 Oct;9(5):408-418
pubmed: 27651445
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
Atherosclerosis. 2010 Apr;209(2):498-503
pubmed: 19880117
Nat Genet. 2016 Oct;48(10):1279-83
pubmed: 27548312
Clin Res Cardiol Suppl. 2019 Apr;14(Suppl 1):5-12
pubmed: 30859385
J Clin Invest. 2011 Sep;121(9):3724-34
pubmed: 21804189
J Am Coll Cardiol. 2015 Sep 15;66(11):1236-1246
pubmed: 26361154
J Am Coll Cardiol. 2017 Feb 14;69(6):692-711
pubmed: 28183512
Nat Genet. 2016 Oct;48(10):1284-1287
pubmed: 27571263
Sci Rep. 2018 Jan 31;8(1):1943
pubmed: 29386597
Biomark Med. 2011 Oct;5(5):673-94
pubmed: 22003918
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
J Intern Med. 2013 Jan;273(1):6-30
pubmed: 22998429
JAMA Cardiol. 2018 Jul 1;3(7):619-627
pubmed: 29926099
J Am Coll Cardiol. 2021 Aug 3;78(5):437-449
pubmed: 34325833
J Clin Lipidol. 2016 Nov - Dec;10(6):1329-1337.e3
pubmed: 27919349
Nat Genet. 1999 Apr;21(4):357-8
pubmed: 10192381
Pathology. 2019 Feb;51(2):155-164
pubmed: 30595508
J Biol Chem. 1997 Nov 28;272(48):30387-99
pubmed: 9374529
Genome Med. 2020 Aug 21;12(1):74
pubmed: 32825847
J Clin Invest. 1994 Apr;93(4):1481-92
pubmed: 8163653
Clin Sci (Lond). 2017 Feb 1;131(4):261-268
pubmed: 28108631
Hum Mol Genet. 1997 Jul;6(7):1099-107
pubmed: 9215681
Science. 2020 Sep 11;369(6509):1318-1330
pubmed: 32913098
J Clin Lipidol. 2019 May - Jun;13(3):402-404
pubmed: 30987918
Clin Chem. 1996 Mar;42(3):436-9
pubmed: 8598109
Circ Genom Precis Med. 2021 Feb;14(1):e003182
pubmed: 33522245
J Am Coll Cardiol. 2013 May 28;61(21):2169-79
pubmed: 23541965
Front Genet. 2012 Mar 15;3:35
pubmed: 22435069
Arterioscler Thromb Vasc Biol. 2021 May 5;41(5):1792-1800
pubmed: 33730874
J Clin Lipidol. 2010 Nov-Dec;4(6):543-7
pubmed: 21122702
J Lipid Res. 1995 Aug;36(8):1721-8
pubmed: 7595093
Circulation. 2020 Jun 2;141(22):1826-1828
pubmed: 32479194
Nat Rev Cardiol. 2019 May;16(5):305-318
pubmed: 30675027
Nucleic Acids Res. 2019 Jan 8;47(D1):D1005-D1012
pubmed: 30445434
JACC Basic Transl Sci. 2020 May 06;5(6):549-557
pubmed: 32613143
J Clin Invest. 1993 Apr;91(4):1630-6
pubmed: 8473506
Bioinformatics. 2011 Aug 1;27(15):2156-8
pubmed: 21653522
J Am Coll Cardiol. 2019 Jul 9;74(1):54-66
pubmed: 31272552
Arterioscler Thromb. 1992 Oct;12(10):1214-26
pubmed: 1390593
Bioinformatics. 2017 Jul 01;33(13):2056-2058
pubmed: 28200055
Fly (Austin). 2012 Apr-Jun;6(2):80-92
pubmed: 22728672
J Clin Invest. 1992 Jul;90(1):52-60
pubmed: 1386087
Nat Genet. 2019 Nov;51(11):1574-1579
pubmed: 31676865
Atherosclerosis. 2003 Jan;166(1):119-27
pubmed: 12482558
JAMA Cardiol. 2020 Oct 06;:
pubmed: 33021622
J Am Coll Cardiol. 2019 Dec 17;74(24):2982-2994
pubmed: 31865966
Arterioscler Thromb Vasc Biol. 2021 Jan;41(1):458-464
pubmed: 33115273
Atherosclerosis. 2017 Sep;264:58-66
pubmed: 28772107
J Clin Endocrinol Metab. 2016 Sep;101(9):3281-7
pubmed: 27218270
Nat Genet. 2018 Sep;50(9):1219-1224
pubmed: 30104762
Gesundheitswesen. 2005 Aug;67 Suppl 1:S26-30
pubmed: 16032514
Nat Genet. 2016 Nov;48(11):1443-1448
pubmed: 27694958
J Clin Lipidol. 2018 May - Jun;12(3):702-710
pubmed: 29574075
J Am Coll Cardiol. 2020 Aug 18;76(7):781-793
pubmed: 32792075
N Engl J Med. 2009 Dec 24;361(26):2518-28
pubmed: 20032323
J Lipid Res. 2020 Jul;61(7):1128-1139
pubmed: 32404332
J Lipid Res. 2017 Sep;58(9):1834-1844
pubmed: 28512139
J Clin Lipidol. 2013 Sep-Oct;7(5):526-30
pubmed: 24079291
Nature. 2021 Feb;590(7845):290-299
pubmed: 33568819
N Engl J Med. 2020 Jan 16;382(3):244-255
pubmed: 31893580
J Am Coll Cardiol. 2012 Aug 21;60(8):722-9
pubmed: 22898070
Atherosclerosis. 2015 Oct;242(2):521-8
pubmed: 26302166
Nucleic Acids Res. 2018 Jan 4;46(D1):D1062-D1067
pubmed: 29165669
J Lipid Res. 2016 Nov;57(11):1953-1975
pubmed: 27677946