Duymus Fahrettin, Kocak Nadir, Özdemir Ebru Marzioğlu, Esin Deniz, Körez Muslu Kazim, Cora Tülün
Department of Medical Genetics, Konya City Hospital, Konya, Turkey.
Department of Medical Genetics, Selcuk University, Konya, Turkey.
Mol Syndromol. 2025 Apr;16(2):128-137. doi: 10.1159/000540898. Epub 2024 Aug 30.
The inducible degrader of low-density lipoprotein (IDOL) receptor, an E3 ubiquitin ligase, was recently identified as a regulator of the LDL receptor (LDLR) pathway. Shortly, IDOL stimulates LDLR degradation through ubiquitination. However, the association of gene variants with plasma lipid levels is controversial. No previous study in the Turkish population has reported the relationship between variants of the gene and low-density lipoprotein cholesterol (LDL-C) levels. Our study aims to investigate the effects of genetic variants in the human IDOL gene, which may be a therapeutic target in human cholesterol metabolism, on LDL-C levels.
We sequenced all coding, critical intronic, and untranslated regions of the IDOL gene in 125 controls (77 women, 48 men) and 125 patients (64 women, 61 men) with definite or probable familial hypercholesterolemia (FH) according to the criteria of the Dutch Lipid Clinic Network, in whom no pathogenic/likely pathogenic LDLR variants are present.
We identified 12 different IDOL gene variants, including the p.(N342S) and p.(G51S), whose association with LDL-C levels has been investigated, and classified them into common and rare variants. A rare variant p.(G51S) was only detected in patients the patient group. We compared the minor allele frequency (MAF) distribution of common variants between patient and control groups and examined the association of their genotypic distribution with plasma LDL-C levels using genetic models (dominant, recessive, overdominant, codominant). There was no statistically significant difference in the parameters of the patient and control groups ( > 0.05).
Our findings suggest that the common IDOL variants we identified do not associate with the LDL-C level in the Turkish population. Rare variants that were not found to be statistically significant in our study, should be emphasized, and supported with further research.
低密度脂蛋白（IDOL）受体诱导降解物是一种E3泛素连接酶，最近被确定为低密度脂蛋白受体（LDLR）途径的调节剂。简而言之，IDOL通过泛素化刺激LDLR降解。然而，基因变异与血脂水平的关联存在争议。此前在土耳其人群中尚无研究报道该基因变异与低密度脂蛋白胆固醇（LDL-C）水平之间的关系。我们的研究旨在调查人类IDOL基因中的遗传变异对LDL-C水平的影响，该基因可能是人类胆固醇代谢的治疗靶点。
我们根据荷兰脂质诊所网络的标准，对125名对照者（77名女性，48名男性）和125名确诊或疑似家族性高胆固醇血症（FH）患者（64名女性，61名男性）的IDOL基因所有编码区、关键内含子区和非翻译区进行了测序，这些患者不存在致病性/可能致病性的LDLR变异。
我们鉴定出12种不同的IDOL基因变异，包括已对其与LDL-C水平的关联进行过研究的p.(N342S)和p.(G51S)，并将它们分为常见变异和罕见变异。仅在患者组中检测到一种罕见变异p.(G51S)。我们比较了患者组和对照组中常见变异的次要等位基因频率（MAF）分布，并使用遗传模型（显性、隐性、超显性、共显性）检查了它们的基因型分布与血浆LDL-C水平的关联。患者组和对照组的参数之间无统计学显著差异（>0.05）。
我们的研究结果表明，我们鉴定出的常见IDOL变异与土耳其人群的LDL-C水平无关。在我们的研究中未发现具有统计学显著性的罕见变异，应予以强调，并通过进一步研究加以支持。
