Role of mitochondria DNA A10398G polymorphism on development of Parkinson's disease: A PRISMA‐compliant meta‐analysis

Abstract Background Parkinson's disease (PD) is characterized by memory loss and multiple cognitive disorders caused primarily by neurodegeneration. However, the preventative effects of the mitochondrial A10398G DNA polymorphism remain controversial. This meta‐analysis comprehensively assessed evidence on the influence of the mitochondrial DNA A10398G variant on PD development. Methods The PubMed, EMBASE, EBSCO, Springer Link, and Web of Science databases were searched from inception to May 31, 2020. We used a pooled model with random effects to explore the effect of A10398G on the development of PD. Stata MP version 14.0 was used to calculate the odds ratios and 95% confidence intervals (CIs) from the eligible studies to assess the impact of mitochondrial DNA A10398G on PD development. Results The overall survey of the populations showed no significant association between mitochondrial DNA A10398G polymorphism (G allele compared to A allele) and PD (odds ratio = 0.85, 95% CI = 0.70–1.04, p = 0.111); however, a significant association between the mutation and PD was observed in the Caucasian population (odds ratio = 0.71, 95% CI = 0.58–0.87, p = 0.001). A neutral effect was observed in the Asian population (odds ratio = 1.10, 95% CI = 0.94–1.28, p = 0.242). Conclusions The results of this meta‐analysis showed the potential protective effect of the mitochondrial DNA A10398G polymorphism on the risk of developing PD in the Caucasian population. Studies with better designs and larger samples with intensive work are required to validate these results.


| Relevant and eligible literature search
Two investigators independently searched the PubMed, EMBASE, EBSCO, Springer Link, and Web of Science databases for relevant literature published through May 2020 using the following keywords: mitochondrial DNA or A10398G, gene polymorphism or variant, and familial Parkinson's disease or familial PD. Human case-control studies set to be searched as references.

| Inclusion and exclusion criteria for the eligible studies
The case-control studies included in this analysis fulfilled four inclusion criteria: (1) explored the effect of mitochondrial DNA polymorphism A10398G on PD, (2) provided odds ratios (ORs) and 95% confidence intervals (CIs) from sufficient allele data, (3) investigated equal numbers of cases and controls, and (4) were written in English and had available full texts.
The exclusion criteria were: (1) case reports, editorials, review articles, or meta-analyses; and (2) investigations of mitochondrial DNA polymorphism A10398G without sufficient data.

| Extraction and assessment of the eligible studies
Two investigators (IST and an anonymous investigator) independently assessed eligible articles and collected the required data. We also discussed with a third reviewer (second anonymous investigator) to resolve disagreement between the two investigators. We extracted and presented the eligible studies as the surname of the first author followed by et al., and recorded the publication year, population ethnicity, and the number of cases and controls. The quality of the eligible studies was evaluated independently by IST and the anonymous investigators according to the Newcastle-Ottawa Scale (NOS). 25 We identified articles of high quality, defined as NOS scores ≥6 stars.

| Ethical statements
This was a literature-based study; thus, no ethical approval was required.

| Statistical analysis
Stata MP, version 14.0 (Stata Corporation) was used to analyze the extracted data. To assess the impact of the relationship between the variant and PD sensitivity, OR and CI were calculated. Statistically significant differences were defined as p < 0.05. Q-and I 2 tests were used to examine the heterogeneity between studies. 26 Furthermore, the relationship between the mitochondrial A10398G DNA variant and PD risk was assessed using the random-effects model of allele data. 27 We also addressed concerns regarding heterogeneity through subgroup analysis stratified by different populations to re-examine the relationship between mitochondrial A10398G DNA | 3 of 7 TZENG variants and PD risk. In addition, we conducted a sensitivity analysis to examine the stability of the results. Funnel plots and Begg's tests were used to explore potential publication bias. We concluded that no trial publication bias was embedded in the meta-analysis (p > 0.05). 28 Table 1

| Sensitivity test and publication bias of the included studies
In the allele model, the sensitivity tests for integrated OR and CI showed no significant changes when removing each study individually. The OR of the meta-analysis also remained stable ( Figure 3).

| DISCUSS ION
Endurance training is a powerful tool to improve health and performance. Physical activity is an effective intervention for many diseases. 29,30 Activating mitochondrial function and exercising muscles are among the most profound adaptations. 31      Due to the amino acid replacement from Thr to Ala, which leads to a transition from A to G, the A10398G ND3 SNP may encode one subunit constituting complex I. 38 The mitochondrial electron transport is catalyzed by a very large enzyme complex I. 39,40 The trivially correlated 10398G allele may improve the expression of complex I. 12 An active complex I may lead to increased ATP synthesis and defend against various PD-related biotoxins. 41 45 Our meta-analysis results were similar to those of a previous meta-analysis. 46 Unlike the metaanalysis by Hua et al., 46 our study additionally included the study by Simon et al. 23 because PD includes familial and sporadic forms.
Caucasian and Asian populations may also exhibit contradictory findings due to their different exposures to environmental factors.