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The COMT Val158Met polymorphism as an associated risk factor for Parkinson's disease in Asian rather than Caucasian populations
Correspondence Address: Source of Support: National Natural Science Foundation of China
None, Conflict of Interest: None DOI: 10.4103/0028-3886.108121
Background: Catechol-O-methyltransferase (COMT) gene has been reported to be associated with the risk of Parkinson's disease (PD). Aims: To evaluate the associations of PD risk with COMT polymorphisms. Materials and Methods: A retrieval of studies that investigated associations between COMT polymorphisms and PD was carried out. Studies were included if they met the eligibility criteria. Statistical Analysis: Data were analyzed using Stata version 12.0. Results: A total of 18 studies including 2926 PD cases and 3151 controls were included. The results showed no significant association with all genotypes and alleles in Caucasians. However in Asians, the homozygote A/A (Odds ratio [OR] =1.51, 95% confidence interval [CI] =1.16-1.98, P =0.002) tends to increase risk of PD, however, the homozygote G/A (OR =0.85, 95% CI =0.74-0.98, P =0.03) may be a slightly protective effect against PD. Conclusions: This study showed that the COMT polymorphisms may be associated with PD in Asians rather than Caucasians. But further studies are needed to confirm our results. Keywords: Catechol-O-methyltransferase, Parkinson′s disease, polymorphism, meta-analysis
Parkinson's disease (PD) is a common movement disorder that results from the progressive loss of dopaminergic neurons in the substantia nigra. [1] The cause of this disease is unknown, however, the available evidence suggests that a combination of oxidative damage, environmental toxins, genetic predisposition, and accelerated aging may ultimately lead to the impairment of the neuron. [2] Early in the course of the disease, various enzymes, which are concerned with dopamine metabolism, such as catechol-O-methyltransferase (COMT), monoamine oxidases (MAO) are involved in the inactivation of the dopamine. [3] COMT is coded by COMT gene, which is located on chromosome 22. [4] Some studies have involved that the Val158Met polymorphism of COMT gene are related to the susceptibility of PD. In contrast, several studies have also found no association between Val158Met polymorphism and risk of PD. Thus as regard to the link between the alleles or gene types of COMT and the risk of developing PD, there is still a dispute. [5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20] In the present study, we assessed the association between COMT gene polymorphisms and risk for PD by conducting a meta-analysis.
Data collection We carried out a retrieval of studies that investigated associations between COMT polymorphisms and PD. The databases that we have searched included Medline (from 1966 to March 2012), Cochrane Library, Google Scholar, and Chinese databases such as the China National Knowledge Infrastructure (CNKI). The Medical Subject Terms, Keywords, and free text words used for this research were: COMT OR Val158Met, polymorphism(s) OR variation, allele(s) OR genotype(s) and PD. We also accomplished hand searches of reviews and articles on this topic. In addition, we performed a further search of reference listed in published original articles. All database searches were restricted to human subjects with no language limitation. Inclusion criteria The inclusion criteria included if (1) type of the study design enrolled in the original articles was case-control study; (2) the data collected included the gender, age data, and studies must have identified all age groups; (3) one or more of the alleles, such as Val (G) or Met (A) was mentioned; (4) genotype frequencies complied with Hardy-Weinberg equilibrium (HWE) in the control group. Data extraction We screened the documents by reading the titles and abstracts. The study was excluded if it clearly did not meet the eligibility criteria. We also filtered the animal studies and duplicated articles. Then we further obtained the full text of those included studies. The following information was extracted from each included study: First author name, date of publication, country or region, ethnicity of the study population; characteristics of study participants. Statistical analysis We calculated whether the genotype distribution of the control group met with the HWE in each study using Chi-square test. The associations between COMT polymorphisms and PD were analyzed by means of odds ratios (ORs) and corresponding 95% confidence intervals (CIs). The forest plots, Chi-square test and I-square (I 2 )_ were used to evaluate the heterogeneity between studies. In general, I 2 was commonly used to test the size of heterogeneity. If I 2 is below 50%, it is considered homogeneous. On the basis of clinical heterogeneity among the included studies, we decided to choose the random effects model or fixed effects model. We analyzed the data using Stata version 12.0 (Stata Corp., College Station, TX, USA).
Study characteristics A total of 251 studies were initially retrieved. We filtered the studies with overlapping data, animal studies, review articles, and studies without controls. Finally, 18 studies met all inclusion criteria. The characteristics of the studies are shown in [Table 1]. A total of 2926 PD cases and 3151 controls in the studies were included. Ten case-control studies were from Asian and eight were from European and North American. By mean of observing P value using the Chi-square test, we checked if the genotype frequencies in included studies met HWE [Table 2]. The genotype frequencies in 18 studies were in HWE (P0 > 0.01). Finally we pooled and analyzed all studies.
Test of heterogeneity In this analysis, we evaluated the homogeneities across the studies using random effects models and fixed effects models simultaneously. The results of homogeneity test across studies are shown in [Table 3] and [Table 4]. In our homogeneity test, all overall effect sizes were not heterogeneous (P > 0.05, I 2 < 50%), and so the fixed effect models were used among studies.
Quantitative data synthesis There was no difference in G/G genotype between cases and controls in overall and subgroup analysis [Table 3] and [Figure 1]. The carriers of A alleles (homozygotes, A/A and heterozygotes, G/A) were not different in overall analysis [Table 3], [Figure 1]. However, our results indicated A/A genotype and G/A genotype had significant associations with PD in Asians rather than Caucasians. Hence in Asians, the homozygotes A/A (OR =1.51, 95% CI 1.16-1.98, P =0.002) tends to increase risk of PD, however, the homozygotes G/A (OR =0.85, 95% CI 0.74-0.98, P =0.03) may be a slightly protective effect against PD.
The results of this analysis indicated the G or A allelic gene was not associated with the risk of PD in overall analysis using fixed effect model [Table 2] and [Table 4]. We also tried to analyze the effect sizes in subgroup by ethnicity. The alleles were not significantly associated with PD [Table 4], [Figure 2] in either Asians or Caucasians.
Sensitivity analysis and publication bias We evaluated the sensitivity by means of selecting two effect sizes models simultaneously and conducting a further analysis by comparing two effect models. The results of the random effect in either overall or subgroups analysis remained similar to fixed effect models [Table 3] and [Table 4]. Because the number of included studies was limited, we tried to use fail-safe number (Nfs) to assess the reliability of our meta-analysis (the results not shown). Apart from allele A, the Nfs 0.05 was negative, which indicated the studies included may prone to publication bias.
This analysis pooled the COMT alleles and genotypes distribution data published in Asians and Caucasians. The analysis for PD showed no significant association with all genotypes and alleles in Caucasians. However in Asians, the A/A genotype might be a potential risk factor for susceptibility to PD, the G/A might be a protective factor to PD to a certain extent. In human COMT gene, Val158Met polymorphism results in amino acid from valine to methionine at position 158. The activity of Val is markedly 3- to 4-fold higher than Met. [18],[23],[24] So far, the G/A polymorphism of COMT gene as a biological marker has been widely applied in the etiology of disease susceptibility. [25],[26] Dopamine is metabolized by MAO and COMT. If activity of COMT is low, the metabolism of dopamine is accomplished by MAO. However, dopamine degradation by MAO is apt to produce more free radicals and hydrogen peroxides, which enhance oxidative stress and damage the nigrostriatal system. Hence genotype A/A may enhance the susceptibility of PD. The data analysis results in Asians supporting the above-mentioned views. However, high activity of COMT can accelerate the degradation of dopamine in the synaptic clefts. It reduces the reuptake in presynaptic neurons, so that the update rate of dopamine speeds up and excessive oxygen free radicals generate. Therefore, as previously described in the studies, the genotype G/G may also increase the risk of PD. [13],[19] But in this meta-analysis, the genotype G/G does not seem to be a genetic risk factor for PD in either Asians or Caucasians, consistent with other previous reports. [5],[14],[18] The genotype G/A has medium activity. The COMT can regulate and maintain the balance of dopamine metabolism and release. As our results, the heterozygous G/A is a protective factor for PD in the Asians. In the European and North American, there is no difference in genotypes distribution and the genotype G/A is the major gene. However, in the East Asians, the G allele accounts for the dominant position and the genotype G/G is the major gene. Due to genetic differences of the Asians and Caucasians, we finished the analysis of the subgroup. Finally we found COMT gene, which has a certain relationship with the Asians rather than Caucasians. In the present analysis, there are several potential limitations. First, we only included 10 studies in Asians and 8 studies in Caucasians. Thus this analysis could not involve other ethnicities, especially Black Africans, so some inevitable biases may produce. Second, because the funnel plots is limited when the included studies is less than 10 and the size in the sample is small, [27] the publication bias in included studies was tested by means of Nfs analysis. The Nfs analysis showed there was a certain publication bias. The main reason may be that the literatures included were mainly published. The gray literatures, which met our inclusion criteria, including conference papers eventually led to a selection bias. In conclusion, this analysis showed that the COMT polymorphisms may be associated with PD in Asians rather than Caucasians. Genotype A/A is associated with increased susceptibility to PD, however, the genotype G/A may decrease PD risk. Further studies are needed to confirm our results.
Our study was partly supported by the Youth Fund of Education Agency of Yunnan Province. We kindly thank the editors and reviewers for their helps. We also thank all authors in the reference for their original works.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]
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