Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Pott, J; Kheirkhah, A; Gadin, JR; Kleber, ME; Delgado, GE; Kirsten, H; Forer, L; Hauck, SM; Burkhardt, R; Scharnagl, H; Loeffler, M; März, W; Thiery, J; Gieger, C; Peters, A; Silveira, A; Hooft, FV; 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. 2024; 15(1): 26
Doi: 10.1186/s13293-024-00602-6
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- Co-Autor*innen der Med Uni Graz
- März Winfried
- Scharnagl Hubert
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- 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 × 10-6), 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Male - administration & dosage
- Humans - administration & dosage
- Female - administration & dosage
- Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage
- Proprotein Convertase 9 - genetics, metabolism
- Genome-Wide Association Study - administration & dosage
- Cholesterol, LDL - genetics
- Oxidoreductases, N-Demethylating - administration & dosage
- Jumonji Domain-Containing Histone Demethylases - administration & dosage
- Find related publications in this database (Keywords)
- PCSK9
- GWAS
- Sex
- Statin
- Interaction