Effects of the PCSK9 C378W Mutation on PCSK9 Levels and Lipid Profiles in Taiwanese Individuals: A Loss-of-Function...

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid metabolism. The rare PCSK9 C378W (rs776752113) mutation influences the level of low-density lipoprotein cholesterol (LDL-C); however, its association with PCSK9 levels remain unclear. Methods: This study investigates the frequency of the C378W mutation and its effects on PCSK9 levels and lipid profiles in 5901 Taiwan Biobank participants, including 1486 individuals with available whole-genome sequencing data. The C378W mutations were detected using a TaqMan genotyping assay and confirmed using direct DNA sequencing. Results: Whole-genome sequencing data revealed a single carrier of the C378W mutation. The TaqMan assay identified seven carriers of the 378W allele (7/5901 [0.119%]). After the exclusion of an individual with a history of hyperlipidemia, six carriers exhibited significantly lower levels of LDL-C (-30.5%) and PCSK9 (-56.4%) than noncarriers (LDL-C: 81.17 ± 21.79 vs. 116.70 ± 30.70 mg/dL [p = 0.0005]; PCSK9: 67.20 ± 14.83 vs. 154.02 ± 45.52 ng/mL [p = 3.59 × 10^-12]. Moreover, carriers exhibited significantly lower levels of total cholesterol (-18.6%) and non-high-density lipoprotein cholesterol (non-HDL-C; -28.4%) than noncarriers (total cholesterol: 157.17 ± 19.30 vs. 193.18 ± 35.22 mg/dL [p = 0.0035]; non-HDL-C: 99.50 ± 20.22 vs. 138.91 ± 34.97 mg/dL [p = 0.0005]). Mediation analysis suggests that the association between the C378W mutation and LDL-C levels persisted even after adjustment for PCSK9 levels. Functional characterization indicates that the C378W mutation impairs protein stability and function. Conclusion: In conclusion, the rare C378W mutation represents a loss-of-function mutation in the Taiwanese population. This variant is independently associated with reduced PCSK9 levels and improved lipid profiles, highlighting its potential cardioprotective role.