Hiroshi Mabuchi1, Atsushi Nohara2, Tohru Noguchi2, Junji Kobayashi2, Masa-aki Kawashiri3, Takeshi Inoue3, Mika Mori3, Hayato Tada3, Chiaki Nakanishi3, Kunimasa Yagi3, Masakazu Yamagishi3, Kousei Ueda4, Tadayoshi Takegoshi5, Susumu Miyamoto6, Akihiro Inazu7, Junji Koizumi8. 1. Department of Lipidology, Graduate School of Medical Science, Kanazawa University, Takara-machi 13-1, Kanazawa 920-8640, Japan. Electronic address: mabuchi@med.kanazawa-u.ac.jp. 2. Department of Lipidology, Graduate School of Medical Science, Kanazawa University, Takara-machi 13-1, Kanazawa 920-8640, Japan. 3. Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan. 4. Komatsu Municipal Hospital, Komatsu, Japan. 5. Fukui Prefectural Hospital, Fukui, Japan. 6. Hokuriku Central Hospital, Oyabe, Japan. 7. Laboratory Science, Graduate School of Medical Science, Kanazawa University, Japan. 8. General Medicine, Graduate School of Medical Science, Kanazawa University, Japan.
Abstract
BACKGROUNDS: Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by hypercholesterolemia, tendon xanthomas, and premature coronary heart disease. FH is caused by mutations of "FH genes," which include the LDL-receptor (LDLR), apolipoprotein B-100 (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9). We evaluated the usefulness of FH gene analysis for diagnosing homozygous FH (homo-FH), particularly in cases caused by gain-of-function (g-o-f) mutations in PCSK9 (PCSK9 E32K). OBJECTIVES: To evaluate the frequency of homo-FH caused by PCSK9 E32K compared with FH due to other genetic causes and to report the phenotypic features of homo-FH caused by PCSK9 E32K. METHODS: Genomic DNA was prepared from white blood cells, and LDLR and PCSK9 mutations were identified using the Invader assay method. RESULTS: Of the 1055 hetero-FH patients, 62 patients (5.9%) carried the PCSK9 E32K mutation, while in the 82 alleles of 41 homo-FH patients, 13 (15.9%) had double mutations of LDLR allele and PCSK9 E32K mutation. Mean plasma total cholesterol (TC) (9.93 ± 2.95 mmol/L, mean ± SD) in true homo-FH cases with PCSK9 E32K or double hetero-FH cases with PCSK9 E32K and LDLR mutations were significantly lower than those in true homo-FH (18.06 ± 4.96 mmol/L) and compound heterozygous cases with LDLR mutations (14.84 ± 1.62 mmol/L). Mean plasma TC concentrations in the 59 hetero-FH cases with PCSK9 E32K (7.21 ± 1.55 mmol/L) were significantly lower than those (8.94 ± 1.53 mmol/L) in the hetero-FH by LDLR mutations. CONCLUSIONS: FH caused by PCSK9 g-o-f mutations is relatively common in Japan and causes a mild type of homo- and hetero-FH compared with FH caused by LDLR mutations.
BACKGROUNDS: Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by hypercholesterolemia, tendon xanthomas, and premature coronary heart disease. FH is caused by mutations of "FH genes," which include the LDL-receptor (LDLR), apolipoprotein B-100 (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9). We evaluated the usefulness of FH gene analysis for diagnosing homozygous FH (homo-FH), particularly in cases caused by gain-of-function (g-o-f) mutations in PCSK9 (PCSK9E32K). OBJECTIVES: To evaluate the frequency of homo-FH caused by PCSK9E32K compared with FH due to other genetic causes and to report the phenotypic features of homo-FH caused by PCSK9E32K. METHODS: Genomic DNA was prepared from white blood cells, and LDLR and PCSK9 mutations were identified using the Invader assay method. RESULTS: Of the 1055 hetero-FHpatients, 62 patients (5.9%) carried the PCSK9E32K mutation, while in the 82 alleles of 41 homo-FHpatients, 13 (15.9%) had double mutations of LDLR allele and PCSK9E32K mutation. Mean plasma total cholesterol (TC) (9.93 ± 2.95 mmol/L, mean ± SD) in true homo-FH cases with PCSK9E32K or double hetero-FH cases with PCSK9E32K and LDLR mutations were significantly lower than those in true homo-FH (18.06 ± 4.96 mmol/L) and compound heterozygous cases with LDLR mutations (14.84 ± 1.62 mmol/L). Mean plasma TC concentrations in the 59 hetero-FH cases with PCSK9E32K (7.21 ± 1.55 mmol/L) were significantly lower than those (8.94 ± 1.53 mmol/L) in the hetero-FH by LDLR mutations. CONCLUSIONS:FH caused by PCSK9 g-o-f mutations is relatively common in Japan and causes a mild type of homo- and hetero-FH compared with FH caused by LDLR mutations.
Authors: Ariel Brautbar; Emili Leary; Kristen Rasmussen; Don P Wilson; Robert D Steiner; Salim Virani Journal: Curr Atheroscler Rep Date: 2015-04 Impact factor: 5.113