Department of Cardiology, Kanazawa University Graduate School of Medicine.
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University.
Circ J. 2019 Aug 23;83(9):1917-1924. doi: 10.1253/circj.CJ-19-0317. Epub 2019 Jul 20.
A substantial proportion of patients clinically diagnosed as having familial hypercholesterolemia (FH) do not manifest causative mutation(s) in the FH genes such asLDLR,APOB, andPCSK9. We aimed to evaluate the effect of rare and deleterious mutation(s) inABCG5/ABCG8on hyper-low-density lipoprotein (LDL) cholesterolemia in individuals who meet the clinical criteria for FH.
We compared the LDL cholesterol (LDL-C) values among 487 subjects with FH; the subjects were grouped according to the presence of mutation(s) in FH andABCG5/ABCG8genes. We identified 276 individuals with a deleterious mutation in 1 FH gene (57%, monogenic FH), but found no causative mutations in 156 individuals (32%, mutation-negative). A total of 37 individuals had deleterious mutations inABCG5orABCG8, but not in FH genes (8%,ABCG5/ABCG8mutation carriers). Among these, 3 individuals had sitosterolemia (0.6%) with double mutations. We also identified 18 individuals with deleterious mutations in an FH gene andABCG5orABCG8(4%,ABCG5/ABCG8-oligogenic FH). Subjects without mutations had significantly higher polygenic scores than those in any other groups. LDL-C levels in oligogenic FH subjects were significantly higher than in the monogenic FH subjects. Moreover, sitosterol/lathosterol levels were significantly affected by those mutations.
The results suggested that rare and deleterious mutations inABCG5/ABCG8contribute substantially to mimicking and exacerbation of the FH phenotype.
相当一部分临床上被诊断为家族性高胆固醇血症 (FH) 的患者并未在 LDLR、APOB 和 PCSK9 等 FH 基因中表现出致病突变。我们旨在评估罕见和有害突变 (s) 在 ABCG5/ABCG8 对符合 FH 临床标准的个体的极低密度脂蛋白 (LDL) 胆固醇血症的影响。
我们比较了 487 名 FH 患者的 LDL 胆固醇 (LDL-C) 值；根据 FH 和 ABCG5/ABCG8 基因是否存在突变将受试者分组。我们在 1 个 FH 基因中发现了 276 个有害突变个体（57%，单基因 FH），但在 156 个个体中未发现致病突变（32%，突变阴性）。共有 37 名个体在 ABCG5 或 ABCG8 中存在有害突变，但在 FH 基因中不存在（8%，ABCG5/ABCG8 突变携带者）。其中，3 名个体存在双突变的甾醇血症（0.6%）。我们还在 1 个 FH 基因和 ABCG5 或 ABCG8 中发现了 18 名个体存在有害突变（4%，ABCG5/ABCG8-寡基因 FH）。无突变的受试者的多基因评分明显高于其他任何组。寡基因 FH 受试者的 LDL-C 水平明显高于单基因 FH 受试者。此外，甾醇/羊毛固醇水平受到这些突变的显著影响。
结果表明，ABCG5/ABCG8 中的罕见和有害突变对模拟和加剧 FH 表型有很大贡献。
