Abstract 18715: Clinical Characteristics of Double Heterozygotes With PCSK9 Gain-of-Function Mutations and LDLR Mutations
PCSK9 gene was found as the third causal gene of familial hypercholesterolemia (FH). Gain-of-function mutations in PCSK9 gene are found in more than 5% of clinical FH in Japan, and this is more frequent than any other countries. We investigated clinical characteristics of gain-of-function PCSK9 mutations as heterozygotes and double heterozygotes with LDLR mutations.
Methods: A total of 982 clinically diagnosed FH including 41 clinical-homozygotes were investigated for LDLR, PCSK9, and APOB gene. High-resolution melting method followed by Sanger were used for point mutation, and multiplex ligation-dependent probe amplification methods were applied for large rearrangements in LDLR.
Results: We identified 12 double heterozygotes with PCSK9 E32K and LDLR mutations, double heterozygotes with PCSK9 V4I and LDLR, 732 heterozygotes with LDLR mutations, 56 heterozygotes with PCSK9 E32K, and 143 individuals without disease causing mutations.
Double heterozygotes with PCSK9 E32K and LDLR mutations showed significantly higher LDL-C than heterozygotes with LDLR mutations. (LDL-C 306±111 vs. 268±73, p<0.05), and three of them were diagnosed as clinical homozygous FH. Double heterozygotes with PCSK9 V4I and LDLR showed slightly higher LDL-C (ns), and none of them were diagnosed as homozygotes. Even 3 of double heterozygotes were diagnosed as clinical homozygotes, they considerably responded to statins because of residual intact LDL receptors.
In comparison between heterozygotes, PCSK9 carriers showed significantly milder LDL-C (LDLR 268±73, PCSK9 198±82, No mutation 198±65 mg/dL, p<0.001). On the other hand, PCSK9 carriers 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 (25%, 41%, 36%, p<0.01). Achilles tendon xanthoma was more frequent in LDLR mutations. Lp(a) levels did not significantly different.
Conclusion: PCSK9 gain-of-function showed mild LDL-C elevation and wider clinical phenotype compare with relatively equal phenotype of LDLR mutation. PCSK9 carriers showed more hypertriglyceridemia, and this can be attributable to previous kinetic report that PCSK9 regulates also VLDL production.
Author Disclosures: A. Nohara: Other Research Support; Modest; Shionogi, Aegerion, Kowa, Synageva. Other Research Support; Significant; Keitai-Kai Medical Crop.. Consultant/Advisory Board; Modest; Sanofi, Amgen. M. Kawashiri: None. H. Tada: None. M. Yoshida: None. M. Mori: None. C. Nakanishi: None. K. Yagi: None. A. Inazu: None. T. Kobayashi: None. M. Yamagishi: None. H. Mabuchi: None.
- © 2016 by American Heart Association, Inc.