Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.
Biol Sex Differ. 2024 Mar 26;15(1):26. doi: 10.1186/s13293-024-00602-6.
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.
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.
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.
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.
前蛋白转化酶枯草溶菌素 9（PCSK9）是脂质代谢的关键因子，女性在其整个生命周期中的血浆水平较高。他汀类药物治疗会影响 PCSK9 水平，并且有证据表明存在性别差异效应。目前尚不清楚这些差异是否可以用遗传因素来解释。
我们对来自六个欧洲独立研究的 PCSK9 水平进行了性别和他汀类药物治疗的全基因组关联荟萃分析（GWAS）（分别为 8936 名女性/11080 名男性，8936 名他汀类药物治疗组/11080 名他汀类药物治疗组）。对一个亚组中存在关联的基因座进行了他汀类药物和性别相互作用的测试，每个基因座均考虑了所有独立信号。然后，使用 PCSK9 基因座上的独立变体在 PCSK9 对低密度脂蛋白胆固醇（LDL-C）水平的分层孟德尔随机化分析（cis-MR）中检测亚组之间因果效应的差异。
我们在至少一个分层亚组中发现了 11 个与 PCSK9 相关的基因座（p<1.0×10），包括 PCSK9 基因座和其他五个脂质基因座：APOB、TM6SF2、FADS1/FADS2、JMJD1C 和 HP/HPR。交互分析显示有 8 个基因座存在性别和/或他汀类药物相互作用。在 PCSK9 基因座上，有 4 个独立信号，其中一个存在显著的性别相互作用，在男性中作用更强（rs693668）。关于他汀类药物治疗，PCSK9 错义突变有两个显著的相互作用：rs11591147 在无他汀类药物治疗的个体中作用更强，rs11583680 在他汀类药物治疗的个体中作用更强。除了复制已知的基因座外，我们还检测到两个新的全基因组显著关联：一个是他汀类药物治疗个体的 6q11.1（在 KHDRBS2 内），另一个是男性的 12q24.22（靠近 KSR2/NOS1），均具有显著的相互作用。在 PCSK9 对 LDL-C 的 MR 中，我们在所有亚组中均观察到了显著的因果估计，但与他汀类药物治疗个体相比，无他汀类药物治疗个体的因果效应明显更强。
我们进行了首次 PCSK9 水平的双分层 GWAS，并确定了多个具有遗传相互作用效应的生物学上合理的基因座。我们的研究结果表明，PCSK9 观察到的性别二态性及其与他汀类药物相关的相互作用具有遗传基础。PCSK9 与 LDL-C 之间因果关系的显著差异表明，PCSK9 抑制剂的剂量存在性别特异性。
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