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Meta-GWAS on PCSK9 concentrations reveals associations of novel loci outside the PCSK9 locus in White populations.
Atherosclerosis 386:117384 (2023)
Background and aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid homeostasis. A few earlier genome-wide association studies (GWAS) investigated genetic variants associated with circulating PCSK9 concentrations. However, uncertainty remains about some of the genetic loci discovered beyond the PCSK9 locus. By conducting the largest PCSK9 meta-analysis of GWAS (meta-GWAS) so far, we aimed to identify novel loci and validate the previously reported loci that regulate PCSK9 concentrations. Methods: We performed GWAS for PCSK9 concentrations in two large cohorts (GCKD (n = 4,963) and KORA F3 (n = 2,895)). These were meta-analyzed with previously published data encompassing together 20,579 individuals. We further conducted a second meta-analysis in statin-naïve individuals (n = 15,390). A genetic risk score (GRS) was constructed on PCSK9-increasing SNPs and assessed its impact on the risk for coronary artery disease (CAD) in 394,943 statin-naïve participants (17,077 with events) of the UK Biobank by performing CAD-free survival analysis. Results: Nine loci were genome-wide significantly associated with PCSK9 concentrations. These included the previously described PCSK9, APOB, KCNA1/KCNA5, and TM6SF2/SUGP1 loci. All imputed SNPs in the PCSK9 locus account for ∼15% of variance of PCSK9 concentrations. We further identified FADS2 as a novel locus that was also found in statin-naïve participants. All imputed SNPs within the FADS2 locus explain ∼1.2% of variance of PCSK9 concentrations. Additionally, four further loci (a region on chromosome 5, SDK1, SPATA16 and HPR) were genome-wide significant in either the main model or the statin-naïve subset. The linear increase in a PCSK9 genetic risk score was associated with 1.41-fold (95%CI 1.16–1.72, p < 0.001) higher risk for incident CAD. Conclusions: We identified five novel loci (FADS2, SPATA16, SDK1, HPR and a region on chromosome 5) for PCSK9 concentrations that would require further research. Additionally, we confirm the genome-wide significant loci that were previously detected.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Cardiovascular Disease ; Fads2 ; Meta-gwas ; Pcsk9; Genetic-variants; Wide Association; Ldl Cholesterol; Expression; Tm6sf2; Liver; Inflammation; Metaanalysis; Regulator; Disease
ISSN (print) / ISBN
0021-9150
e-ISSN
1879-1484
Zeitschrift
Atherosclerosis
Quellenangaben
Band: 386,
Artikelnummer: 117384
Verlag
Elsevier
Verlagsort
Amsterdam
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Epidemiology II (EPI2)
Förderungen
DFG
Bayer Pharma Aktiengesellschaft
H2020-IMI2 Consortium BEAt-DKD
KfH Foundation
German Ministry of Education and Research
Austrian Research Fund (FWF)
Bayer Pharma Aktiengesellschaft
H2020-IMI2 Consortium BEAt-DKD
KfH Foundation
German Ministry of Education and Research
Austrian Research Fund (FWF)