Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation

被引:74
作者
Mabuchi, Hiroshi [1 ]
Nohara, Atsushi [1 ]
Noguchi, Tohru [1 ]
Kobayashi, Junji [1 ]
Kawashiri, Masa-aki [2 ]
Inoue, Takeshi [2 ]
Mori, Mika [2 ]
Tada, Hayato [2 ]
Nakanishi, Chiaki [2 ]
Yagi, Kunimasa [2 ]
Yamagishi, Masakazu [2 ]
Ueda, Kousei [3 ]
Takegoshi, Tadayoshi [4 ]
Miyamoto, Susumu [5 ]
Inazu, Akihiro [6 ]
Koizumi, Junji [7 ]
机构
[1] Kanazawa Univ, Grad Sch Med Sci, Dept Lipidol, Kanazawa, Ishikawa 9208640, Japan
[2] Kanazawa Univ, Grad Sch Med Sci, Div Cardiovasc Med, Kanazawa, Ishikawa 9201192, Japan
[3] Komatsu Municipal Hosp, Komatsu, Japan
[4] Fukui Prefectural Hosp, Fukui, Japan
[5] Hokuriku Cent Hosp, Oyabe, Japan
[6] Kanazawa Univ, Grad Sch Med Sci, Lab Sci, Kanazawa, Ishikawa 9201192, Japan
[7] Kanazawa Univ, Grad Sch Med Sci, Kanazawa, Ishikawa 9201192, Japan
关键词
Homozygous familial hypercholesterolemia (Homo-FH); Heterozygous-FH (Hetero-FH); LDL-receptor; PCSK9; AUTOSOMAL-DOMINANT HYPERCHOLESTEROLEMIA; LDL-RECEPTOR GENE; CHOLESTEROL; SPECTRUM; PLASMA;
D O I
10.1016/j.atherosclerosis.2014.06.005
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
引用
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页码:54 / 61
页数:8
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