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Proprotein Convertase Subtilisin Kexin type 9 (PCSK9), comprises 12 exons, encoded for an enzyme which plays a critical role in the regulation of circulating low density lipoprotein. The gain-of-function (GOF) mutations aggravate the degradation of LDL receptors, resulting in familial hypercholesterolemia (FH), while loss-of-function (LOF) mutations lead to higher levels of the LDL receptors, lower the levels of LDL cholesterol, and preventing from cardiovascular diseases. It is noted that, previous publications related to the mutations of PCSK9 were not always unification. Therefore, this study aims to present the spectrum and distribution of PCSK9 gene mutations by a meta-analysis. A systematic literature analysis was conducted based on previous studies published by using different keywords. The weighted average frequency of PCSK9 mutation was calculated and accessed by MedCalc®. A total of 32 cohort studies, that included 19,725 familial hypercholesterolemia blood samples, were enrolled in the current study. The analysis results indicated that, based on the random-effect model, the weighted prevalence of PCSK9 mutation was 5.67% (95%CI = 3.68–8.05, p &lt; 0.0001). The prevalence of PCSK9 GOF mutations was 3.57% (95%CI = 1.76–5.97, p &lt; 0.0001) and PCSK9 LOF mutations was 6.05% (95%CI = 3.35–9.47, p &lt; 0.0001). Additionally, the first and the second exon were identified as the hot spot of mutation occurred in PCSK9. Both GOF and LOF mutations have a higher proportion in Asia and Africa compared with other regions. The GOF PCSK9 p.(Glu32Lys) and LOF PCSK9 p.(Leu21dup/tri) were dominant in the Asia region with the proportion as 6.58% (95%CI = 5.77–7.47, p = 0.62) and 16.20% (95%CI = 6.91–28.44, p = 0.0022), respectively. This systematic analysis provided scientific evidence to suggest the mutation of PCSK9 was related to the metabolism of lipoprotein and atherosclerotic cardiovascular disease.

Proprotein Convertase Subtilisin/Kexin Type 9 Gene Variants in Familial Hypercholesterolemia: A Systematic Review and Meta-Analysis