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Sex and statin-related genetic associations at the PCSK9 gene locus: results of genome-wide association meta-analysis.
- Source :
-
Biology of sex differences [Biol Sex Differ] 2024 Mar 26; Vol. 15 (1), pp. 26. Date of Electronic Publication: 2024 Mar 26. - Publication Year :
- 2024
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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.<br />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.<br />Results: We identified 11 loci associated with PCSK9 in at least one stratified subgroup (p < 1.0 × 10 <superscript>-6</superscript> ), 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.<br />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.<br /> (© 2024. The Author(s).)
Details
- Language :
- English
- ISSN :
- 2042-6410
- Volume :
- 15
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Biology of sex differences
- Publication Type :
- Academic Journal
- Accession number :
- 38532495
- Full Text :
- https://doi.org/10.1186/s13293-024-00602-6