Department of Cardiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel Center for Research Prevention and Treatment of Atherosclerosis, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel; Center for Research Prevention and Treatment of Atherosclerosis, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, University College London, 5 University Street, London, WC1E 6JF, UK.
Atherosclerosis. 2017 Feb;257:55-63. doi: 10.1016/j.atherosclerosis.2016.12.021. Epub 2016 Dec 18.
Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the genes for LDL receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type9 (PCSK9). The purpose of the current investigation was to define the current spectrum of mutations causing FH in Israel.
New families were collected through the MEDPED (Make Early Diagnosis Prevent Early Death) FH program. Molecular analysis of the LDLR, PCSK9 and APOB genes was done using High Resolution Melt and direct sequencing in 67 index cases. A 6-SNP LDL-C gene score calculation for polygenic hypercholesterolaemia was done using TaqMan genotyping.
Mean serum cholesterol was 7.48 ± 1.89 mmol/L and the mean serum LDL-C was 5.99 ± 1.89 mmol/L. Mutations in the LDLR and APOB gene were found in 24 cases (35.8%), with 16 in LDLR, none in PCSK9 and one, p.(R3527Q), in the APOB gene, which is the first APOB mutation carrier identified in the Israeli population. Of the LDLR mutations, two were novel; p.(E140A) and a promoter variant, c.-191C > A. The c.2479G > A p.(V827I) in exon 17 of the LDLR gene was found in 8 patients (33.3% of the mutations) with modestly elevated LDL-C, but also in a compound heterozygous patient with a clinical homozygous FH phenotype, consistent with this being a "mild" FH-causing variant. A significantly higher 6-SNP LDL-C score was found in mutation-negative cases compared with a normal Caucasian cohort (p = 0.03), confirming that polygenic inheritance of common LDL-C raising SNPs can produce an FH phenocopy.
The results indicate a different spectrum of genetic causes of FH from that found previously, in concordance with the heterogeneous and changing origins of the Israeli population, and confirm that a polygenic cause is also contributing to the FH phenotype in Israel.
家族性高胆固醇血症（FH）是一种常染色体显性疾病，由 LDL 受体（LDLR）、载脂蛋白 B（APOB）和前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9（PCSK9）基因的突变引起。本研究的目的是确定导致以色列 FH 的突变的当前谱。
通过 MEDPED（早期诊断预防早期死亡）FH 计划收集新的家族。对 67 名指数病例的 LDLR、PCSK9 和 APOB 基因进行高分辨率融解和直接测序的分子分析。使用 TaqMan 基因分型计算多基因高胆固醇血症的 6-SNP LDL-C 基因评分。
平均血清胆固醇为 7.48±1.89mmol/L，平均血清 LDL-C 为 5.99±1.89mmol/L。在 24 例（35.8%）中发现 LDLR 和 APOB 基因的突变，其中 16 例在 LDLR 中，PCSK9 中无突变，APOB 基因中有一个突变，p.（R3527Q），这是在以色列人群中首次发现的 APOB 突变携带者。在 LDLR 突变中，有两个是新的；p.（E140A）和一个启动子变异，c.-191C＞A。在 LDLR 基因外显子 17 中的 c.2479G＞A p.（V827I）在 8 例患者（突变的 33.3%）中发现，LDL-C 略有升高，但也在一个具有临床纯合 FH 表型的复合杂合患者中发现，这与这种“轻度”FH 致病变异一致。与正常白种人群相比，在突变阴性病例中发现了显著更高的 6-SNP LDL-C 评分（p=0.03），证实常见 LDL-C 升高 SNP 的多基因遗传可产生 FH 表型。
结果表明 FH 的遗传原因与先前发现的不同，与以色列人口的异质性和变化的起源一致，并证实多基因原因也导致了以色列 FH 表型。
