Aghajanpour-Mir Mohsen, Amjadi-Moheb Fatemeh, Dadkhah Tahereh, Hosseini Seyed Reza, Ghadami Elham, Assadollahi Ehsan, Akhavan-Niaki Haleh, Ahmadi Ahangar Alijan
Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran.
Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Mol Biol Rep. 2019 Feb;46(1):1033-1041. doi: 10.1007/s11033-018-4561-5. Epub 2018 Dec 17.
Clusterin (CLU) is the third most important associated risk gene in cognitive disorders. Regarding the controversy about the association of CLU rs11136000 with mild cognitive impairment (MCI), the aim of this study was to investigate a putative association of CLU rs11136000 with MCI as well as the serum biological factors with a special attention to the age as a main dimension of a multifactorial elderly disease in an Iranian elderly cohort in which the mentioned association was not previously investigated. The study also checked the association between diabetes and MCI in this population. A population of 418 individuals containing 236 MCI and 192 control subjects was recruited from the Amirkola health and aging population cohort. Serum biological indexes were assessed by biochemical and enzyme-linked immunosorbent assay, and rs11136000 genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. Bioinformatics analyses were used to identify the putative effect of rs11136000 on the secondary structure of RNA and chromatin location in different cell lines and tissues. Type 2 diabetes was present with a higher proportion in the MCI group in comparison with the control group (P = 0.041). The frequency of the C allele of CLU rs11136000 was significantly different between cases and controls and was associated with MCI risk (OR 1.79, P = 0.019). Under a dominant genetic model, the CC genotype showed a predisposing effect in individuals aged ≥ 75 years (OR 3.33, P = 0.0004). Interestingly, under an over-dominant model, the CT genotype had a protective effect in this population (OR 4.52, P = < 0.0001). We also found a significant association between the genotypes and high-density lipoprotein (HDL) levels in MCI patients (P = 0.0004). Bioinformatics analysis showed that rs11136000 is located in the transcribed region without any regulatory features such as being enhancer or insulator. Also, the T>C transition of CLU rs11136000 could not cause significant mRNA folding (P = 0.950). Contrary to other studies on Asian populations, this study demonstrated an association between rs11136000 and MCI in an elderly Iranian population. This study also suggests that an age-dependent approach to the previous studies may be performed in order to revise the previous belief in this geographical area. The rs11136000 genotypes in combination with HDL levels and knowledge about diabetes background may be used as a predictive medicine tool for cognitive disorders.
簇集素（CLU）是认知障碍中第三个最重要的相关风险基因。关于CLU rs11136000与轻度认知障碍（MCI）关联的争议，本研究的目的是调查CLU rs11136000与MCI之间的假定关联以及血清生物学因素，特别关注年龄这一多因素老年疾病的主要维度，在一个伊朗老年队列中，此前尚未对上述关联进行研究。该研究还检查了该人群中糖尿病与MCI之间的关联。从阿米科拉健康与老龄化人群队列中招募了418名个体，其中包括236名MCI患者和192名对照受试者。通过生化和酶联免疫吸附测定评估血清生物学指标，并使用聚合酶链反应 - 限制性片段长度多态性进行rs11136000基因分型。生物信息学分析用于确定rs11136000对不同细胞系和组织中RNA二级结构和染色质定位的假定影响。与对照组相比，MCI组中2型糖尿病的比例更高（P = 0.041）。CLU rs11136000的C等位基因频率在病例组和对照组之间存在显著差异，并且与MCI风险相关（OR 1.79，P = 0.019）。在显性遗传模型下，CC基因型在年龄≥75岁的个体中显示出易感性作用（OR 3.33，P = 0.0004）。有趣的是，在超显性模型下，CT基因型在该人群中具有保护作用（OR 4.52，P = <0.0001）。我们还发现MCI患者的基因型与高密度脂蛋白（HDL）水平之间存在显著关联（P = 0.0004）。生物信息学分析表明，rs11136000位于转录区域，没有任何增强子或绝缘子等调控特征。此外，CLU rs11136000的T>C转换不会导致显著的mRNA折叠（P = 0.950）。与其他关于亚洲人群的研究相反，本研究证明了rs11136000与伊朗老年人群中MCI之间的关联。该研究还表明，可能需要对先前的研究采用年龄依赖性方法，以修正该地理区域先前的观点。rs11136000基因型与HDL水平以及糖尿病背景知识相结合，可作为认知障碍的预测医学工具。
