Informative combination of CLU rs11136000, serum HDL levels, diabetes, and age as a new piece of puzzle-picture of predictive medicine for cognitive disorders

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 aged75years (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.