Lipid Clinic at the Interdisciplinary Metabolism Center, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Atherosclerosis. 2016 Oct;253:88-93. doi: 10.1016/j.atherosclerosis.2016.08.037. Epub 2016 Aug 26.
Autosomal-dominant familial hypercholesterolemia (FH) is characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and a dramatically increased risk to develop cardiovascular disease (CVD). Mutations in three major genes have been associated with FH: the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB), and the proprotein convertase subtilisin/kexin 9 gene (PCSK9). Here we investigated the frequency and the spectrum of FH causing mutations in Germany.
We screened 206 hypercholesterolemic patients, of whom 192 were apparently unrelated, for mutations in the coding region of the genes LDLR, PCSK9 and the APOB [c.10580G > A (p.Arg3527Gln)]. We also categorized the patients according to the Dutch Lipid Clinic Network Criteria (DLCNC) in order to allow a comparison between the mutations identified and the clinical phenotypes observed. Including data from previous studies on German FH patients enabled us to analyse data from 479 individuals.
Ninety-eight FH causing variants were found in 92 patients (nine in related patients and 6 patients with two variants and likely two affected alleles), of which 90 were located in the LDLR gene and eight mutations were identified in the APOB gene (c.10580G > A). No mutation was found in the PCSK9 gene. While 48 of the LDLR mutations were previously described as disease causing, we found 9 new LDLR variants which were rated as "pathogenic" or "likely pathogenic" based on the predicted effect on the corresponding protein. The proportions of different types of LDLR mutations and their localization within the gene was similar in the group of patients screened for mutations here and in the combined analysis of 479 patients (current study/cases from the literature) and also to other studies on the LDLR mutation spectrum, with about half of the variants being of the missense type and clustering of mutations in exons 4, 5 and 9. The mutation detection rate in the 35 definite and 45 probable FH patients (according to DLCNC) was 77.1% and 68.9%, respectively. The data show a similar discriminatory power between the DLCNC score (AUC = 0.789 (95% CI 0.721-0,857)) and baseline LDL-C levels (AUC = 0.799 (95% CI = 0.732-0.866)).
This study further substantiates the mutation spectrum for FH in German patients and confirms the clinical and genetic heterogeneity of the disease.
常染色体显性遗传性高胆固醇血症（FH）的特征是血浆低密度脂蛋白胆固醇（LDL-C）水平升高，心血管疾病（CVD）风险显著增加。已有三种主要基因的突变与 FH 相关：低密度脂蛋白受体基因（LDLR）、载脂蛋白 B 基因（APOB）和前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9 基因（PCSK9）。本研究旨在调查德国 FH 致病突变的频率和谱。
我们对 206 名高胆固醇血症患者进行了 LDLR、PCSK9 和 APOB 基因编码区的突变筛查[c.10580G > A（p.Arg3527Gln）]。我们还根据荷兰脂质诊所网络标准（DLCNC）对患者进行了分类，以便比较鉴定的突变与观察到的临床表型。纳入之前德国 FH 患者的研究数据，我们共分析了 479 例个体的数据。
在 92 例患者（9 例为相关患者，6 例为两种变异且可能有两种受影响的等位基因）中发现了 98 种 FH 致病变异，其中 90 种位于 LDLR 基因中，8 种突变位于 APOB 基因中（c.10580G > A）。PCSK9 基因未发现突变。虽然 48 种 LDLR 突变之前被认为是致病的，但我们发现了 9 种新的 LDLR 变异，根据对相应蛋白的预测影响，这些变异被评为“致病性”或“可能致病性”。在此筛选突变的患者组和 479 例患者（当前研究/文献中的病例）的综合分析以及其他 LDLR 突变谱研究中，不同类型 LDLR 突变及其在基因内的定位比例相似，大约一半的变异为错义型，突变集中在 4、5 和 9 外显子。根据 DLCNC，35 例确定的和 45 例可能的 FH 患者的突变检出率分别为 77.1%和 68.9%。数据显示，DLCNC 评分（AUC=0.789（95%CI 0.721-0.857））和基线 LDL-C 水平（AUC=0.799（95%CI=0.732-0.866））之间具有相似的判别能力。
本研究进一步证实了德国 FH 患者的突变谱，并证实了该疾病的临床和遗传异质性。
