Rare and Deleterious Mutations in ABCG5/ABCG8 Genes Contribute to Mimicking and Worsening of Familial Hypercholesterolemia Phenotype
Rare and Deleterious Mutations in ABCG5/ABCG8 Genes Contribute to Mimicking and Worsening of Familial Hypercholesterolemia Phenotype
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DOI：
10.1253/circj.cj-19-0317
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发表时间：
2019-09-01
影响因子：
3.3
通讯作者：
Kawashiri, Masa-aki
中科院分区：
文献类型：
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作者：
Tada, Hayato;Okada, Hirofumi;Kawashiri, Masa-aki
背景资料：临床诊断为家族性高胆固醇血症（FH）的相当大比例的患者在FH基因（如LDLR、APOB和PCSK 9）中未表现出致病突变。我们的目的是评估的影响，罕见的和有害的突变（S）在ABCG 5/ABCG 8对高低密度脂蛋白（LDL）胆固醇血症的个人谁符合FH的临床标准。方法和结果：我们比较了低密度脂蛋白胆固醇（LDL-C）值之间的487例FH的受试者，受试者进行分组，根据FH和ABCG 5/ABCG 8基因突变的存在。我们确定了276个个体在1个FH基因中有有害突变（57%，单基因FH），但在156个个体中没有发现致病突变（32%，突变阴性）。共有37名个体在ABCG 5或ABCG 8中有有害突变，但在FH基因中没有（8%，ABCG 5/ABCG 8突变携带者）。其中，3人有谷甾醇血症（0.6%）与双突变。我们还鉴定了18名FH基因和ABCG 5或ABCG 8（4%，ABCG 5/ABCG 8-寡基因FH）中存在有害突变的个体。没有突变的受试者的多基因评分显著高于其他组。寡基因FH受试者的LDL-C水平显著高于单基因FH受试者。此外，谷甾醇/脂甾醇水平显着影响这些mutations.Conclusions：结果表明，罕见的和有害的突变ABCG 5/ABCG 8大大有助于模仿和加剧FH表型。
Background: A substantial proportion of patients clinically diagnosed as having familial hypercholesterolemia (FH) do not manifest causative mutation(s) in the FH genes such as LDLR, APOB, and PCSK9. We aimed to evaluate the effect of rare and deleterious mutation(s) in ABCG5/ABCG8 on hyper-low-density lipoprotein (LDL) cholesterolemia in individuals who meet the clinical criteria for FH.Methods and Results: 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 and ABCG5/ABCG8 genes. 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 in ABCG5 or ABCG8, but not in FH genes (8%, ABCG5/ABCG8 mutation carriers). Among these, 3 individuals had sitosterolemia (0.6%) with double mutations. We also identified 18 individuals with deleterious mutations in an FH gene and ABCG5 or ABCG8 (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.Conclusions: The results suggested that rare and deleterious mutations in ABCG5/ABCG8 contribute substantially to mimicking and exacerbation of the FH phenotype.