==== Front Ann Saudi MedAnn Saudi MedAnnals of Saudi Medicine0256-49470975-4466King Faisal Specialist Hospital and Research Centre 2465854910.5144/0256-4947.2014.12asm-1-12Original ArticleThe relationship between monoamine oxidase B (MAOB) A644G polymorphism and Parkinson disease risk: a meta-analysis Liu Ying abWang Zhiyun bZhang Benshu a a Department of Neurology, General Hospital, Tianjin Medical University, Tianjin, China b Department of Neurology, Tianjin First Center Hospital, Tianjin Medical University, Tianjin, ChinaCorrespondence: Benshu Zhang, 153 Anshan Rd., Tianjin 30052, China, +86 022 23626407, drliuying@126.comJan-Feb 2014 34 1 12 17 Copyright © 2014, Annals of Saudi Medicine2014This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.BACKGROUND AND OBJECTIVES Many studies were conducted to assess the relationship between Monoamine oxidase B (MAOB) A644G polymorphism and susceptibility to Parkinson disease (PD). However, the results were inconsistent and inconclusive. DESIGN AND SETTINGS A meta-analysis was conducted from all published studies on the associations between monoamine oxidase B (MAOB) A644G polymorphism and Parkinson disease. METHODS In this present study, the possible relationship between MAOB A644G polymorphism and PD risk was assessed by a meta-analysis. Eligible articles were identified for the period up to March 2013. Pooled odds ratios (OR) with 95% confidence intervals (CI) were appropriately derived from fixed-effects models. RESULTS Twenty case–control studies with a total of 2846 cases and 3508 controls were eligible. In a recessive model, MAOB A644G polymorphism was associated with PD risk (OR=1.32, 95% CI 1.18–1.47, P<.001). Subgroup analyses by ethnicity and gender also found significant relationships between this polymorphism and PD risk. CONCLUSION This meta-analysis suggested that MAOB A644G polymorphism may be associated with PD development. ==== Body Parkinson disease (PD) is a neurodegenerative disorder with unknown causes. More than 1 million people in the United States have PD, and PD affects approximately 1 in 100 Americans older than 60 years.1 Although PD typically presents in a sporadic fashion, between 10% and 15% of PD patients have a family history of the disease, indicating that there is a strong genetic basis for this disease.2 Monoamine oxidase B (MAOB) is one of the primary enzymes regulating metabolism of neurotransmitters such as dopamine. It catalyzes the production of hydrogen peroxide, and it activates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to MPP+ a toxic metabolite that can cause parkinsonism.3 Steventon et al. showed that patients with PD had higher platelet MAOB activity than control individuals. 4 In addition, MAOB activity increases with age as does predisposition toward PD, which has also been linked to increased oxidative stress.5 Furthermore, it is well documented that MAOB inhibition may prevent degeneration of the dopaminergic system in PD.6 Therefore, MAOB may play a critical role in the development of PD. The MAOB gene is located on the X chromosome. It contains a single-stranded conformational polymorphism in intron 13, a transitional conversion of adenine (A) to guanine (G) at 36 bp upstream from the 5′ end of exon 14 (A644G, rs1799836). This polymorphism is associated with varying enzyme activity. The G allele of MAOB A644G polymorphism is associated with lower brain MAOB activity, and A allele is associated with higher mRNA levels of MAOB.7 A number of papers investigated the relationship between this polymorphism and PD risk. However, the results remained inconclusive.8–27 Meta-analysis is a useful method for investigating the relationship s between genetic factors and diseases, because a quantitative approach is used to combine the results from different studies on the same topic, thereby providing more reliable conclusions. Thus, we performed a meta-analysis to clarify the relationship of MAOB A644G polymorphism with PD risk. To our knowledge, this is the most comprehensive meta-analysis of the relationship between MAOB A644G polymorphism and PD risk. METHODS Search for publications In our meta-analysis, we searched the articles using the search terms “MAOB,” “monoamine oxidase B,” “Parkinson disease,” and “polymorphism” in the PubMed, Embase, and CNKI databases, and the last search updated on March 2013. Additional studies were identified by a hand search of references of original studies or review articles on the relationship between MAOB A644G polymorphism and PD risk. No publication date or language restrictions were imposed. Inclusion and exclusion criteria The following inclusion criteria were used: (1) the study should have evaluated the relationship between MAOB A644G polymorphism and PD risk, (2) the study should have had a case–control design, and (3) sufficient data should have been provided to calculate odds ratios (OR) and 95% confidence intervals (CI). Studies were excluded if any of the following conditions applied: (1) irrelevant to PD, MAOB, or MAOB A644G polymorphism and PD risk, (2) abstract or review, (3) genotype frequencies not reported, (4) non-clinical study, and (5) studies repeated studies or overlapped publications. Data extraction Two investigators independently extracted data and reached a consensus on the following characteristics of the selected studies: the first author’s name, year of publication, country, ethnicity of the study population, gender, genotyping method, and numbers of cases and controls with various genotypes. Statistical analysis The strength of relationship between MAOB A644G polymorphism and PD risk was accessed by calculating ORs with 95% CIs. For this meta-analysis, we examined the recessive genetic model (AA [A] vs AG + GG [G]) because allele A is a risk allele for PD, and data were commonly presented either in this format or convertible to this format. The random-effects model (the DerSimonian and Laird method) was used. A chi-square test was used to determine if genotype distribution of the female control population reported conformed to Hardy-Weinberg equilibrium (HWE) (P<.05 was considered significant). Heterogeneity assumption was checked by the I2 statistic to quantify the proportion of the total variation towing to heterogeneity, and I2 value less than 50% indicates a lack of heterogeneity among studies. Subgroup analyses were performed by ethnicity, gender, and smoking status. Cumulative meta-analysis was done. Furthermore, sensitivity analysis was performed by sequential omission of individual studies. Galbraith plot was used to spot the outliers that were the sources of heterogeneity. Funnel plot and Egger test were used to detect publication bias.28 Analyses were performed using STATA 11.0 software (StataCorp LP, College Station, Texas, USA). RESULTS Characteristics of studies A total of 20 case–control studies (Figure 1) with 6354 subjects on the relationship between MAOB A644G polymorphism and PD risk were included for this meta-analysis.8–27 The study involved 8 studies of Caucasian population and 12 studies of Asian population. All studies indicated that the distribution of genotypes in the female controls was consistent with HWE. The characteristics of each case–control study and the genotype in each case–control study are presented in Tables 1 and 2. Results of meta-analyses As shown in Figure 2, the overall OR was 1.32 (95% CI 1.18–1.47), and the Z-test value for the overall effect was 4.80 (P<.001) for the AA (A) vs AG + GG (G). Subgroup analysis by ethnicity was performed. For ethnicity, the populations were stratified into 2 groups: Asian (1865 cases and 2069 controls) and Caucasian (981 cases and 1439 controls). Significant relationships with PD risk in these populations were observed: Asian (OR=1.28, 95% CI 1.10–1.49, P=.001) and Caucasian (OR=1.37, 95% CI 1.15–1.62, P<.001). Besides, subgroup analyses by gender also found significant relationships between MAOB A644G polymorphism and PD risk in females and males (Table 2). With regard to the cumulative meta-analysis, evidence was observed to support a significant relationship of MAOB A644G polymorphism with the susceptibility to PD (Figure 3). As shown in Figure 4, sensitivity analysis did not influence the result excessively by omitting any single study. Funnel plot and Egger test were both performed to access the publication bias of this meta-analysis. The shape of the funnel plot seemed symmetrical, and P values of the Egger test was .116 (Figure 5), providing statistical evidence of the funnel plot symmetry. DISCUSSION This present meta-analysis investigated the relationship between MAOB A644G polymorphism and PD risk. Twenty case–control studies with a total of 6354 subjects were eligible. At the overall analysis, MAOB A644G polymorphism seemed to be associated with PD risk. In addition, subgroup analyses by ethnicity and gender also found significant relationships. Moreover, to investigate the stability of the result, we performed sensitivity analyses. The removal of each study did not alter the result, suggesting the reliability of our result. The cumulative meta-analysis showed a trend of significant relationship between MAOB A644G polymorphism and the PD risk as data accumulated each year. Again, this procedure proved that our result was robust. Thus, results from this meta-analysis suggested that MAOB A644G polymorphism was significantly associated with PD risk. MAOB plays an important role in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. Increased levels of MAOB mRNA and enzymatic activity have been reported in platelets from patients with PD.4 Additionally, Jakubauskiene et al. indicated that enhanced MAOB protein levels in platelets might be used as a disease marker of PD.29 Several DNA polymorphisms in the MAOB gene have been described. The only single-nucleotide polymorphism found in all human populations is the G/A dimorphism in the intron 13 sequence. The molecular analysis of MAOB polymorphism demonstrated that MAOB A644G polymorphism leads to an alterative MAOB activity.7 Thus, we hypothesized that MAOB A644G polymorphism could influence the susceptibility to PD. Our results supported a genetic relationship between this polymorphism and susceptibility to PD. One of the major concerns in a sound meta-analysis is the degree of heterogeneity that exists between the component studies because non-homogeneous data are liable to result in misleading results. In the present study, the I2 statistics was carried out to test the significance of heterogeneity. Moderate heterogeneity between studies was observed in overall comparisons. In an attempt to find the sources of heterogeneity, subgroup analysis was performed. The heterogeneity was significantly reduced in the subgroup analysis by gender. Moreover, we re-analyzed the relationship in the female and male subgroups; the conclusions were consistent. Another important issue for any meta-analysis is publication bias owing to the selective publication of reports. In the current study, funnel plot and Egger test were performed to evaluate this problem. Both the shape of funnel plots and the statistical results did not show publication bias. Some possible limitations in this meta-analysis should be acknowledged. First, only the published studies that were included in the selected electronic databases were identified; it is possible that some relevant published or unpublished studies may have been missed. Second, the effect of gene–gene and gene–environment interactions was not addressed in this meta-analysis because of the limited available data. Third, our meta-analysis was based on the unadjusted OR estimates because not all published studies presented adjusted ORs. In conclusion, this meta-analysis suggests that MAOB A644G polymorphism may be associated with PD development. Further studies can assess the possible gene–environment and gene–gene interactions in the relationship between this polymorphism and PD risk. Figure 1 Flow of study identification, inclusion, and exclusion. Figure 2 Meta-analysis for the relationship between the MAOB A644G polymorphism and PD risk. Figure 3 Cumulative meta-analysis of relationship between the MAOB A644G polymorphism and PD risk. Figure 4 Sensitivity analysis for the MAOB A644G polymorphism and PD risk. Figure 5 Funnel plot for publication bias test in the meta-analysis investigating the relationship between the MAOB A644G polymorphism and PD risk. Table 1 Characteristics of the case–control studies included in meta-analysis. First author Year Country Ethnicity Gender Case Control Case Control Genotyping number (n) number (n) AA (A) AG + GG (G) AA (A) AG + GG (G) Method Kurth 1993 USA Caucasian M, F 64 177 25 39 36 141 PCR-SSCP Morimoto 1995 Japan Asian M, F 83 76 60 23 54 22 PCR-SSCP Costa 1997 USA Caucasian M, F 62 79 26 36 23 56 PCR-SSCP Hwang 1997 China Asian M, F 65 108 49 16 76 32 PCR-SSCP Checkoway 1998 USA Caucasian M, F 82 118 52 30 58 60 PCR-SSCP Mellick 1999 Australia Caucasian M, F 80 110 30 50 36 74 PCR-SSCP Shao 2000 China Asian M, F 126 136 66 65 62 74 PCR-SSCP Wu 2001 China Asian M, F 220 191 37 183 17 174 PCR-SSCP Hernán 2002 USA Caucasian M, F 214 449 86 128 196 253 Allele-specific PCR Kelada 2002 USA Caucasian M, F 186 296 106 80 138 158 PCR-SSCP Tan 2003 Singapore Asian M, F 230 241 171 59 176 65 PCR-SSCP Jiang 2004 China Asian M, F 266 154 207 59 114 40 PCR-SSCP Białecka 2005 Poland Caucasian M, F 210 152 100 110 63 89 PCR-SSCP Singh 2008 India Asian M, F 70 100 30 37 33 37 PCR-SSCP Gu 2010 China Asian M, F 176 354 153 23 323 31 DHPLC Wang 2010 China Asian M, F 125 66 88 37 34 32 PCR-SSCP Kiyohara 2011 Japan Asian M, F 238 369 192 46 273 96 PCR-SSCP Li 2011 China Asian M, F 166 170 111 55 103 67 PCR-RFLP Torkaman-Boutorabi 2012 Iran Caucasian M, F 103 70 75 28 44 26 PCR-RFLP Zeng 2012 China Asian M, F 95 104 67 28 71 33 PCR-RFLP M: male, F: female, MF: male and female, PCR: polymerase chain reaction, SSCP: single-stranded conformational polymorphism, RFLP: restriction fragment length polymorphism, DHPLC: denaturing high-performance liquid chromatography. Table 2 Summary of different results of the association between MAOB A644G polymorphism and the risk of Parkinson disease. Comparison Sample size No. Test of association Heterogeneity Case Control Studies OR (95% CI) Z P value Model c2 P value I2 (%) AA (A) vs AG+GG (G) Overall 2846 3508 20 1.32(1.18–1.47) 4.80 <.001 F 24.45 .18 22.0 AA (A) vs AG+GG (G) Asian 1865 2069 12 1.28(1.10–1.49) 3.22 .001 F 13.25 .28 17.0 AA (A) vs AG+GG (G) Caucasian 981 1439 8 1.37(1.15–1.62) 3.62 <.001 F 10.80 .15 35.0 A vs G Male 1038 1143 12 1.49(1.22–1.81) 3.97 <.001 F 4.29 .96 0 AA vs AG+GG Female 764 970 12 1.32(1.06–1.64) 2.45 .01 F 6.99 .80 0 F: Fixed-effects model. ==== Refs REFERENCES 1 Fritsch T Smyth KA Wallendal MS Hyde T Leo G Geldmacher DS Parkinson Disease: Research Update and Clinical Management South Med J 2012 105 650 6 23211499 2 Zimprich A Genetics of Parkinson’s disease and essential tremor Curr Opin Neurol 2011 24 318 23 21734494 3 Langston JW Epidemiology versus genetics in Parkinson’s disease: progress in resolving an age-old debate Ann Neurol 1998 44 S45 S52 9749572 4 Steventon G Sturman S Heafield M Waring R Napier J Williams A Platelet monoamine oxidase-B activity in Parkinson’s disease J Neural Transm Park Dis Dement Sect 1989 1 255 61 2597311 5 Kumar MJ Andersen JK Perspectives on MAO-B in aging and neurological disease: Where do we go from here? 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