Elsevier

Behavioural Brain Research

Volume 322, Part B, 30 March 2017, Pages 362-367
Behavioural Brain Research

Research report
Gene- gene interaction between CYP2J2 and PPAR -γ gene on late-onset Alzheimer’s disease in the eastern Chinese Han population

https://doi.org/10.1016/j.bbr.2016.07.010Get rights and content

Highlights

  • The first study to examine the combined effects of CYP2J2 and PPAR γ on LOAD risk.

  • Haplotype analysis on association between CYP2J2, PPAR γ and LOAD risk.

  • Independent effects of CYP2J2, PPAR γ single nucleotide polymorphism and LOAD risk in a Chinese population.

Abstract

Aims

To investigate the impact of PPAR -γ and CYP2J2 gene single nucleotide polymorphisms (SNPs) and gene- gene interactions on late-onset Alzheimer’s disease (LOAD) risk in Chinese Han population.

Methods

A total of 880 participants (514 males, 366 females), with a mean age of 81.7 ± 15.9 years old are selected, including 430 LOAD patients and 450 normal participants. Generalized multifactor dimensionality reduction (GMDR) is used to examine interaction among six SNPs, odds ratio (OR) and 95% confident interval (95%CI) are calculated by Logistic regression model.

Results

Logistic regression analysis showed that increased LOAD risks are associated with T allele of the rs1155002 polymorphism, adjusted OR (95%CI) = 1.46 (1.12–1.90), and T allele of the rs890293 polymorphism, adjusted OR (95%CI) = 1.65 (1.30–2.06), and G allele of the rs1805192 polymorphism, adjusted OR (95%CI) = 1.70 (1.25–2.27). We also found a potential gene–gene interaction between rs890293 and rs1805192. Participants with GT or TT of rs890293 and CG or GG of rs1805192 genotype have the highest LOAD risk, compared to participants with GG of rs890293 and CC of rs1805192 genotype, OR (95%CI) = 2.22 (1.63 –2.85), after covariates adjustment.

Conclusions

rs1155002, rs890293 and rs1805192 polymorphism are associated with increased LOAD risk. Participants with GT or TT of rs890293 and CG or GG of rs1805192 genotype have the highest LOAD risk.

Introduction

Alzheimer’s disease (AD) is the most common form of dementia and a complex disease associated with accumulation of b-amyloid (Ab) plaques and neurofibrillary tangles, which is associated with synapse loss and neurodegeneration leading to memory impairment and other cognitive problems [1]. Currently, the prevalence of AD is more than 35 million people worldwide; out of them, 6 million are in China [2]. Clinically, AD can be divided into early-onset (<65 years, EOAD) and late-onset (≥65 years, LOAD) forms, and LOAD is more common type of AD. The heritability for LOAD is predicted to be as high as 80% in twin and family studies [3]. However, till now, the etiology and pathogenesis of LOAD are still not clear, and many studies argue that AD develops as a result of complex interactions between multiple genetic and environmental factors [4]. So it is necessary to find and validate biomarkers for AD prevention, especially for LOAD, which has a strong genetic component [5]. Recently, several genes are identified by positional mapping, targeted gene analysis and genome-wide analysis [5], [6], including PPAR -γ and CYP2J2 gene [6], [7].

In humans, CYP2J2 is one of the predominant CYP epoxygenase isoforms, and is abundantly expressed in the heart and many regions of the brain, especially in the cerebral cortex and hippocampus [8], which correlates with distribution in the brains of AD patients [9]. CYP2J2 is located on human chromosome 1p31.3–31.2 [10], and one of the most relevant polymorphisms in terms of functional importance is rs890293 (G/T), which is located at -50 bp in the proximal CYP2J2 promoter region [11], [12]. It has been shown that rs890293 is associated with susceptibility to various diseases. To our knowledge, till now, just one study [6] focused on the association between CYP2J2 gene polymorphisms and LOAD risk in Chinese population, in this case-control study, the authors examined the possible association of the rs890293 SNP in CYP2J2 with susceptibility to LOAD in the Chinese Han population. PPARγ is another LOAD related gene which is more reported previously [13], [14], [15], [16], [17]. Recently, some studies reported that PPAR -γ can regulate amyloidogenic pathways, reduce amyloid β protein (Aβ) deposition by repressing β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) promoter activity, and increasing the rate of amyloid precursor protein degradation via ubiquitination [13], [14]. Activation of PPAR -γ could also improve mitochondrial function, which is the basis of beneficial effects on memory and cognition in AD patients [15]. Both PPAR -γ and CYP2J2 have important function in inflammation regulation [4], [16], which is known to play a critical role in the pathogenesis of chronic neurodegenerative disease in general, and in AD in particular [17]. Taken together, the above studies suggest that PPAR -γ could represent a potential candidate gene for AD. However, results on association between PPAR -γ and LOAD are inconsistent [18], [19]. So the aim of this study is to investigate the impact of PPAR -γ and CYP2J2 gene single nucleotide polymorphisms (SNPs) and additional gene- gene interaction on LOAD risk based on Chinese Han population.

Section snippets

Participants

This is a case-control study. Participants are consecutively recruited between January 2009 and November 2014 from Second Affiliated Hospital of Zhengzhou University. Clinical diagnosis of probable AD is made according to the revised criteria of National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRDA) [20], participants with advanced, severe, progressive, or unstable infectious, metabolic, immunologic,

Results

A total of 880 participants (514 males, 366 females) are selected, including 430 LOAD patients and 450 normal participants. The mean age of all participants is 81.7 ± 15.9 years, Participants characteristics stratified by cases and controls are shown in Table 2. The distribution of alcohol consumption is significantly different between cases and controls, and drinking rate is higher in cases than that in controls. The mean of FPG, TG, HDL and APOE level are significantly different between cases

Discussion

In the current study, we investigated the impact of PPAR -γ and CYP2J2 gene polymorphism on LOAD risk in Chinese Han population; we found that LOAD risks are significantly higher in carriers of T allele in rs1155002 polymorphism than those with CC genotype, and higher in carriers of T allele in rs890293 polymorphism than those with GG genotype. In addition, we also found LOAD risk is also significantly higher in carriers of G allele in rs1805192 polymorphism than those with CC genotype.

Conflict of interest

There is no conflict of interest.

Acknowledgements

The writing of this paper is supported by Second Affiliated Hospital of Zhengzhou University and PLA 148 Hospital. We thank all the partners and staffs who help us in the process of this study.

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