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Coassin, S.* ; Chemello, K.* ; Khantalin, I.* ; Forer, L.* ; Döttelmayer, P.* ; Schönherr, S.* ; Grüneis, R.* ; Chong-Hong-Fong, C.* ; Nativel, B.* ; Ramin-Mangata, S.* ; Gallo, A.* ; Roche, M.* ; Mühlegger, B.* ; Gieger, C. ; Peters, A. ; Zschocke, J.* ; Marimoutou, C.* ; Meilhac, O.* ; Lamina, C.* ; Kronenberg, F.* ; Blanchard, V.* ; Lambert, G.*

Genome-wide characterization of a highly penetrant form of hyperlipoproteinemia associated with genetically elevated cardiovascular Risk.

Circ. Genom. Precis. Med. 15:e003489 (2022)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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 LPA locus. The extreme Lp(a) phenotype segregated with the presence of a short apo(a) isoform containing 21 Kringle IV domains. This allele was characterized by the presence of three rare strongly Lp(a) increasing single nucleotide polymorphisms and a significantly increased load of oxidized phospholipids per Lp(a) particle. An Lp(a) GRS consisting of 48 single nucleotide polymorphisms that represent 2001 genome-wide significant LPA single nucleotide polymorphisms, efficiently captured the hyper-Lp(a) phenotype and discriminated affected and nonaffected individuals with great accuracy. The genome-wide GRS for CAD, encompassing 6.6 million single nucleotide polymorphisms, was very high for most family members (>97.5 percentile of the reference population), but this observation was no longer valid when the contribution of the LPA locus was omitted. 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, LPA can be a major locus driving a very high CAD GRS. This underpins the large contribution of the LPA locus to the cardiovascular genetic risk in families.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Apolipoproteins ; Coronary Artery Disease ; Lipids ; Lipoprotein (a) ; Risk Factors
ISSN (print) / ISBN 2574-8300
e-ISSN 2574-8300
Zeitschrift Circulation Genomic and precision medicine
Quellenangaben Band: 15, Heft: 2, Seiten: , Artikelnummer: e003489 Supplement: ,
Verlag Lippincott Williams & Wilkins
Verlagsort Philadelphia, Pa.
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epidemiology II (EPI2)
Förderungen Federal Ministry of Education & Research (BMBF)
Fondation de France
French National Research Agency (ANR)
Region Reunion (Saint-Denis, Reunion, France)
European Union (European Regional Development Fund INTERREG V)
Austrian Atherosclerosis Society
Austrian Science Fund (FWF)