Elsevier

Neuroscience Letters

Volume 650, 22 May 2017, Pages 25-32
Neuroscience Letters

Research article
NR4A2 genetic variation and Parkinson's disease: Evidence from a systematic review and meta-analysis

https://doi.org/10.1016/j.neulet.2017.01.062Get rights and content

Highlights

  • Comprehensively quantified the impact of all the reported 24 variants of NR4A2 on Parkinson's disease risk.

  • Made a comprehensive meta-analysis of 2 SNPs (rs35479735 and rs12803) in case–control studies.

  • The NR4A2 rs35479735 polymorphisms significantly associated with PD risk.

Abstract

Introduction

The homo sapiens nuclear receptor subfamily 4, group A (NR4A2) genetic variation has been implicated as a risk factor for Parkinson's disease (PD). Nevertheless, the results are inconclusive. We conducted a comprehensive systematic review and meta-analysis to quantify the impact of NR4A2 variation on the risk of PD.

Methods

All eligible case–control studies published up to June 2016 by searching Pubmed, OVID, EBSCO, PsycINFO, ISI Web of Knowledge, Chinese Biomedical Literature Database and China Academic Journals Database were identified. Pooled odds ratio (OR) with 95% confidence interval (CI) were used to access the strength of the association in fixed- or random-effects model.

Results

Eighteen studies reported 24 genetic variants with a total of 6150 cases and 5919 controls were included. Twelve studies for NR4A2 rs35479735 polymorphism and 4 studies for rs12803 were available for meta-analysis. A significant association was observed for rs35479735 under the homozygous model (OR = 1.31, 95% CI: 1.10–1.56, P = 0.003), whereas no significant association for rs12803 was detected. In subgroup analysis stratified by ethnicity, age onset and familial history, we found no significant association except one in sporadic PD subgroup under the recessive (OR = 3.30, 95% CI: 1.23–8.84, P = 0.02) and homozygous model (OR = 3.43, 95% CI: 1.26–9.33, P = 0.02) for rs35479735.

Conclusion

The study comprehensively evaluated the association of NR4A2 variation with PD, and the results failed to demonstrate that the NR4A2 polymorphisms significantly associated with PD except for rs35479735, suggesting that more studies are needed to elucidate if NR4A2 is a risk of PD.

Introduction

Parkinson's disease (PD), the second most common neurodegenerative disease, is a complex multifactor disease marked by extensive neuropathology in brain with selective yet prominent and progressive loss of midbrain dopamine neurons [33]. Although the cause of PD remains elusive, there are increasing evidences suggesting that dysfunction of some transcription factors for the differentiation and survival of midbrain dopamine neurons may be involved in development of PD [35], [39], [56]. Among them, nuclear receptor subfamily 4, group A, member 2 (NR4A2, also known as Nurr1) is one of the most extensively studied.

NR4A2, a member of the nuclear receptor superfamily of transcription factors, is expressed predominantly in the central nervous system, especially in substantia nigra, ventral tegmental area and limbic areas [24], [44], and subsequently expressed highly in olfactory bulb, hippocampus, temporal cortex, subiculum, cerebellum, posterior hypothalamus [41], and in peripheral lymphocytes [34]. Evidence have indicated that NR4A2 is essential for the development, migration and survival of dopaminergic neurons [3], [24], [42], [45], [58] through the way of regulating tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter 2 [21], [46], [48], Nurr1/CoREST [43] and Ret signaling pathway [55]. Thus, NR4A2 has been suggested as a potential genetic risk factor for dopamine-related disorders [12], [28], [29].

The important role of NR4A2 plays in dopaminergic development has been underscored by identification of several mutations that were only found in PD patients [27], [29], [61]. The mutations (-291Tdel, -245T->G and c.-309C>T) resulted in a marked decrease in NR4A2 mRNA levels in transfected cell lines and in lymphocytes of affected individuals, leading to the downregulation of genes involved in the development and maintenance of the nervous system and synaptic transmission [29], [47], [61]. However, the results remain conflicting rather than conclusive. Some of these mutations have been found in controls and not been found in other cohorts of PD individuals [2], [14], [17], [32], [38], [50], [59], [65] leading to the speculation that NR4A2 does not play a role in PD at all [14]. Therefore, we performed a systematic review and meta-analysis to address the possible association between NR4A2 genetic variation and the risk of PD.

Section snippets

Literature collection

The systematic review was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement [37]. A comprehensive literature search of PubMed, OVID, EBSCO, PsycINFO, ISI Web of Knowledge, Chinese Biomedical Literature Database and China Academic Journals Database were conducted up to June 2016 by two investigators independently. The search strategy was (“Parkinson disease” or “Parkinsons disease” or “Parkinson's disease” or “Parkinsonism” or PD) and

Study characteristics

A total of 335 potentially relevant studies were retrieved with the initial search of databases. Twenty-five studies were preliminarily identified for further evaluation. Two conference proceedings [11], [27] were excluded because of overlapping data with another study [32]. Another 5 studies were discarded because of insufficient published genotype data [11], [17], improper control participants [22] or without case–control design [40]. Therefore, a total of 18 studies [1], [2], [4], [12], [13]

Discussion

The human NR4A2 gene, mapping to chromosome 2q22-23, is about 8.3 kb long and consists of 8 exons and 7 introns [18], [53]. NR4A2 is considered as a crucial regulator for expression of several genes involved in PD pathology [7], [49]. The Nurr1-null mice failed to generate mDA neurons, leading to 98% decrease of DA in the striatum [3], [19], [26], and increased the vulnerability of mDA neurons to MPTP-induced injury [20], [25], [54]. Moreover, NR4A2 expression is decreased in the brain and in

Conclusions

We conducted a comprehensive systematic review of the eligible studies and pooled the available data related to potential links between NR4A2 genetic variation and PD risk. The overall results failed to demonstrate that the NR4A2 polymorphisms significantly associated with PD except for NR4A2 rs35479735, suggesting that more studies are needed to elucidate if NR4A2 is a risk of PD. Due to the given limitations above, well-designed studies with larger sample size, well-matched controls and

Contributors

Conceived and designed the experiments: Hongmei Liu; Searched for and selected the publications: Hongbo Liu, Juanjuan Ren, Ping Jiang; Extract and analyzed the data: Ting Li, Jane Cui, Yingmei Fu; Wrote and revised the paper: Hongmei Liu, Hongbo Liu; Supervised the study: Shunying Yu, Chunbo Li. All authors read and approved the final manuscript.

Conflict of interest

None.

Acknowledgments

We are grateful to Dr. Olaf Riess for his kindly providing the original data. This work was supported partly by Grant from the Shanghai Key Laboratory of Psychotic Disorders (13dz2260500), Shanghai Clinical Center for Mental Disorders (2014), the Shanghai Health System Leadership in Health Research Program (XBR2011005), Shanghai Natural Science Fund Project (14ZR1435700), Natural Science Foundation of Shanghai Jiaotong University School of Medicine (14XJ10079), Shanghai Jiaotong University

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