Predicting proprotein convertase subtilisin kexin type-9 loss of function mutations using plasma PCSK9 concentration

Area of Science:

• Biochemistry
• Genetics
• Clinical Diagnostics

Background:

• Low plasma proprotein convertase subtilisin kexin type-9 (PCSK9) levels are linked to PCSK9 loss-of-function (LOF) mutations.
• Current detection methods like gene sequencing are costly and time-consuming.
• A simpler predictive test for PCSK9 LOF mutations is needed to guide genetic testing.

Purpose of the Study:

• To evaluate the diagnostic accuracy of plasma PCSK9 concentration in identifying PCSK9 LOF mutations.
• To compare plasma PCSK9 concentration against genotyping as the gold standard.
• To assess if combining plasma PCSK9 and LDL-C levels improves mutation prediction.

Main Methods:

• Retrospective analysis of 1412 French-Canadian participants.
• Genotyping for PCSK9 R46L and InsLEU LOF mutations.
• Plasma PCSK9 concentration measurement via ELISA.
• Determination of optimal PCSK9 cutoff using Youden index.
• Analysis of combined PCSK9 and LDL-C predictive value.

Main Results:

• Plasma PCSK9 showed moderate accuracy (AUC 0.71) for R46L mutation detection (71% sensitivity, 70% specificity at 70 ng/mL).
• Combining PCSK9 and LDL-C improved R46L detection accuracy (AUC 0.75).
• Plasma PCSK9 concentration did not effectively detect the InsLEU mutation.

Conclusions:

• Plasma PCSK9 combined with LDL-C may aid in predicting specific PCSK9 LOF mutations like R46L.
• This combined approach may not be effective for predicting other mutations, such as InsLEU.
• Further research is needed to refine predictive models for various PCSK9 LOF mutations.