Mabuchi Hiroshi, Nohara Atsushi, Noguchi Tohru, Kobayashi Junji, Kawashiri Masa-aki, Inoue Takeshi, Mori Mika, Tada Hayato, Nakanishi Chiaki, Yagi Kunimasa, Yamagishi Masakazu, Ueda Kousei, Takegoshi Tadayoshi, Miyamoto Susumu, Inazu Akihiro, Koizumi Junji
Department of Lipidology, Graduate School of Medical Science, Kanazawa University, Takara-machi 13-1, Kanazawa 920-8640, Japan.
Department of Lipidology, Graduate School of Medical Science, Kanazawa University, Takara-machi 13-1, Kanazawa 920-8640, Japan.
Atherosclerosis. 2014 Sep;236(1):54-61. doi: 10.1016/j.atherosclerosis.2014.06.005. Epub 2014 Jun 26.
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).
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.
Genomic DNA was prepared from white blood cells, and LDLR and PCSK9 mutations were identified using the Invader assay method.
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.
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.
家族性高胆固醇血症（FH）是一种常染色体显性疾病，其特征为高胆固醇血症、肌腱黄色瘤和早发性冠心病。FH由“FH基因”的突变引起，这些基因包括低密度脂蛋白受体（LDLR）、载脂蛋白B - 100（APOB）或前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）。我们评估了FH基因分析在诊断纯合子FH（homo - FH）中的作用，特别是在由PCSK9功能获得性（g - o - f）突变（PCSK9 E32K）引起的病例中。
评估与其他遗传原因导致的FH相比，由PCSK9 E32K引起的homo - FH的发生率，并报告由PCSK9 E32K引起的homo - FH的表型特征。
从白细胞中提取基因组DNA，使用侵入检测法鉴定LDLR和PCSK9突变。
在1055例杂合子FH患者中，62例（5.9%）携带PCSK9 E32K突变，而在41例homo - FH患者的共82个等位基因中，13个（15.9%）具有LDLR等位基因双突变和PCSK9 E32K突变。携带PCSK9 E32K的真正homo - FH病例或同时携带PCSK9 E32K和LDLR突变的双杂合子FH病例的平均血浆总胆固醇（TC）（9.93±2.95 mmol/L，平均值±标准差）显著低于真正的homo - FH（18.06±4.96 mmol/L）和携带LDLR突变的复合杂合子病例（14.84±1.62 mmol/L）。59例携带PCSK9 E32K的杂合子FH病例的平均血浆TC浓度（7.21±1.55 mmol/L）显著低于由LDLR突变引起的杂合子FH病例（8.94±1.53 mmol/L）。
在日本，由PCSK9功能获得性突变引起的FH相对常见，与由LDLR突变引起的FH相比，会导致一种轻度类型的纯合子和杂合子FH。
