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

Joachim Thiery, Ferdinand Van't Hooft, Jesper R Gadin, Azin Kheirkhah, Annette Peters, Winfried März, Markus Loeffler, Christian Gieger, Markus Scholz, Florian Kronenberg, Janne Pott, Graciela E Delgado, Marcus E Kleber, Lukas Forer, Hubert Scharnagl, Angela Silveira, Ralph Burkhardt, Stefanie M Hauck, Holger Kirsten

Journal: Biology of sex differences 2024;15(1):26

PMID: 38532495

Free Full Text on BioMed Central View on PubMed

Abstract

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), 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.

Address: Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. [email protected].; MRC Biostatistics Unit, University of Cambridge, Cambridge, UK. [email protected].; Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria.; Division of Cardiovascular Medicine, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital Solna, Solna, Sweden.; Vth Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.; SYNLAB MVZ Humangenetik Mannheim, Mannheim, Germany.; Vth Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.; Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.; LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.; Metabolomics and Proteomics Core, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.; LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.; Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany.; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.; Vth Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.; SYNLAB Academy, Synlab Holding Deutschland GmbH, Mannheim and Augsburg, Germany.; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.; Faculty of Medicine, University of Kiel, Kiel, Germany.; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.; Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. [email protected].; LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany. [email protected].

DOI: 10.1186/s13293-024-00602-6