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Pott, J.* ; Kheirkhah, A.* ; Gådin, J.R.* ; Kleber, M.E.* ; Delgado, G.E.* ; Kirsten, H.* ; Forer, L.* ; Hauck, S.M. ; Burkhardt, R.* ; Scharnagl, H.* ; Loeffler, M.* ; März, W.* ; Thiery, J.* ; Gieger, C. ; Peters, A. ; Silveira, A.* ; Hooft, F.V.* ; Kronenberg, F.* ; Scholz, M.*

Sex and statin-related genetic associations at the PCSK9 gene locus: Results of genome-wide association meta-analysis.

Biol. Sex Differ. 15:26 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold
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BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player of lipid metabolism with higher plasma levels in women throughout their life. Statin treatment affects PCSK9 levels also showing evidence of sex-differential effects. It remains unclear whether these differences can be explained by genetics. METHODS: We performed genome-wide association meta-analyses (GWAS) of PCSK9 levels stratified for sex and statin treatment in six independent studies of Europeans (8936 women/11,080 men respectively 14,825 statin-free/5191 statin-treated individuals). Loci associated in one of the strata were tested for statin- and sex-interactions considering all independent signals per locus. Independent variants at the PCSK9 gene locus were then used in a stratified Mendelian Randomization analysis (cis-MR) of PCSK9 effects on low-density lipoprotein cholesterol (LDL-C) levels to detect differences of causal effects between the subgroups. RESULTS: We identified 11 loci associated with PCSK9 in at least one stratified subgroup (p < 1.0 × 10-6), including the PCSK9 gene locus and five other lipid loci: APOB, TM6SF2, FADS1/FADS2, JMJD1C, and HP/HPR. The interaction analysis revealed eight loci with sex- and/or statin-interactions. At the PCSK9 gene locus, there were four independent signals, one with a significant sex-interaction showing stronger effects in men (rs693668). Regarding statin treatment, there were two significant interactions in PCSK9 missense mutations: rs11591147 had stronger effects in statin-free individuals, and rs11583680 had stronger effects in statin-treated individuals. Besides replicating known loci, we detected two novel genome-wide significant associations: one for statin-treated individuals at 6q11.1 (within KHDRBS2) and one for males at 12q24.22 (near KSR2/NOS1), both with significant interactions. In the MR of PCSK9 on LDL-C, we observed significant causal estimates within all subgroups, but significantly stronger causal effects in statin-free subjects compared to statin-treated individuals. CONCLUSIONS: We performed the first double-stratified GWAS of PCSK9 levels and identified multiple biologically plausible loci with genetic interaction effects. Our results indicate that the observed sexual dimorphism of PCSK9 and its statin-related interactions have a genetic basis. Significant differences in the causal relationship between PCSK9 and LDL-C suggest sex-specific dosages of PCSK9 inhibitors.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Gwas ; Interaction ; Pcsk9 ; Sex ; Statin; R/bioconductor Package; Trans-eqtls; Identification; Expression; Efficacy; Biobank; Pathway; Complex; Safety; Gwas
ISSN (print) / ISBN 2042-6410
e-ISSN 2042-6410
Journal Biology of Sex Differences
Quellenangaben Volume: 15, Issue: 1, Pages: , Article Number: 26 Supplement: ,
Publisher BMC
Publishing Place Campus, 4 Crinan St, London N1 9xw, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) CF Metabolomics & Proteomics (CF-MPC)
Institute of Epidemiology II (EPI2)
Grants Bayer Pharma Aktiengesellschaft (AG)
European Union
Helmholtz Zentrum Munchen
HI-MAG project "Serum proteome biomarkers as mediators of cardiometabolic disease development" of the Medical Faculty of the University Leipzig
Free State of Saxony
European Regional Development Fund (ERDF)
Leipzig Research Center for Civilization Diseases (LIFE)
Swedish Heart-Lung Foundation
Swedish Research Council
Leducq Foundation
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
H2020-IMI2 Consortium BEAt-DKD (Biomarker Enterprise to Attack Diabetic Kidney Disease)
KfH Foundation for Preventive Medicine
German Ministry of Education and Research
Austrian Research Fund (FWF)
German Federal Ministry of Education and Research (BMBF)
United Kingdom Research and Innovation Medical Research Council
Wellcome Trust
Projekt DEAL