Abstract 17990: Common PCSK9 Gain-of-function E32K Variant Carriers Reveal Milder LDL-C but Higher TG Elevation Compared with LDLR Mutations

Background: Proprotein convertase subtilisin kexin type 9 (PCSK9) gene is the third causal gene of familial hypercholesterolemia (FH), and is now an emerging therapeutic target. We have found Gain-of-function mutation E32K in PCSK9 gene is common in Japanese FH. We investigated clinical characteristics of gain-of-function PCSK9 variant carriers. Methods: A total of 940 Clinically diagnosed FH heterozygotes were investigated for LDLR, PCSK9, and APOB gene. High-resolution melting (HRM) method followed by Sanger sequence were used for point mutation, and multiplex ligation-dependent probe amplification methods were applied for large rearrangements in LDLR. Fasting lipid levels without lipid-lowering drugs were analyzed. Results: LDLR mutations were identified in 732 patients (78%) and 10% of them were large rearrangements. PCSK9 E32K mutation was identified in 56 patients (6%). No APOB mutations causing FH were identified, and 143 patients showed no known FH-gene mutations. LDLR mutation carriers showed significantly higher LDL-C (LDLR 268±73, PCSK9 198±82, No mutation 198±65 mg/dL, p <0.001) and higher apoB (183±51, 130±49, 148±42 mg/dL, p <0.001) compared with other two groups. On the other hand, PCSK9 and No mutation group had higher TG compared with LDLR mutations (126±94, 150±84, 145±74 mg/dL, p <0.05 in log-transformed TG). Hypertriglyceridemia was common in PCSK9 mutation (25%, 41%, 36%, p <0.01). HDL-C was higher in No mutation group (47±15, 51±51, 55±27 mg/dL, p <0.01). Achilles tendon xanthoma was more frequent in LDLR mutations. Lp(a) levels did not significantly different with PCSK9 mutation. Results: PCSK9 gain-of-function mutation E32K showed mild LDL-C elevation, but with frequent hypertriglyceridemia. This result will support basic reports that PCSK9 regulates not only LDL-R degradation but also VLDL metabolism.