Atormac
Neurology India
menu-bar5 Open access journal indexed with Index Medicus
  Users online: 3113  
 Home | Login 
About Editorial board Articlesmenu-bullet NSI Publicationsmenu-bullet Search Instructions Online Submission Subscribe Videos Etcetera Contact
  Navigate Here 
 Search
 
  
 Resource Links
  »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
  »  Article in PDF (845 KB)
  »  Citation Manager
  »  Access Statistics
  »  Reader Comments
  »  Email Alert *
  »  Add to My List *
* Registration required (free)  

 
  In this Article
 »  Abstract
 » Introduction
 »  Materials and Me...
 » Results
 » Discussion
 » Acknowledgment
 »  References
 »  Article Figures
 »  Article Tables

 Article Access Statistics
    Viewed2884    
    Printed74    
    Emailed0    
    PDF Downloaded62    
    Comments [Add]    
    Cited by others 9    

Recommend this journal

 


 
Table of Contents    
ORIGINAL ARTICLE
Year : 2013  |  Volume : 61  |  Issue : 1  |  Page : 12-16

The COMT Val158Met polymorphism as an associated risk factor for Parkinson's disease in Asian rather than Caucasian populations


Department of Physiology, Kunming Medical University, Kunming, Yunnan, China

Date of Submission15-Aug-2012
Date of Decision11-Oct-2012
Date of Acceptance10-Dec-2012
Date of Web Publication4-Mar-2013

Correspondence Address:
Lu Lechun
1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming 650500, Yunnan, P.R
China
Login to access the Email id

Source of Support: National Natural Science Foundation of China None, Conflict of Interest: None


DOI: 10.4103/0028-3886.108121

Rights and Permissions

 » Abstract 

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


How to cite this article:
Lechun L, Yu S, Pengling H, Changqi H. The COMT Val158Met polymorphism as an associated risk factor for Parkinson's disease in Asian rather than Caucasian populations. Neurol India 2013;61:12-6

How to cite this URL:
Lechun L, Yu S, Pengling H, Changqi H. The COMT Val158Met polymorphism as an associated risk factor for Parkinson's disease in Asian rather than Caucasian populations. Neurol India [serial online] 2013 [cited 2020 Feb 28];61:12-6. Available from: http://www.neurologyindia.com/text.asp?2013/61/1/12/108121



 » Introduction Top


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.


 » Materials and Methods Top


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).


 » Results Top


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.
Table 1: Characteristics of studies investigating the association between catechol-O-methyltransferase gene polymorphisms in parkinson's disease


Click here to view
Table 2: Distribution of catechol-O-methyltransferase genotypes and allelic frequencies in patients with and without parkinson's disease


Click here to view


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.
Table 3: Meta - analysis of catechol-O-methyltransferase genotypes frequencies in participants with and without parkinson's disease


Click here to view
Table 4: Meta - analysis of catechol-O-methyltransferase allelic frequencies in participants with and without parkinson's disease


Click here to view


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.
Figure 1: Meta-analysis for the association between PD susceptibility and (a) genotype G/G vs. others, (b) genotype G/A vs. others, (c) genotype A/A vs. others

Click here to view


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.
Figure 2: Meta-analysis for the association between PD susceptibility and allele G vs.A

Click here to view


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.


 » Discussion Top


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.


 » Acknowledgment Top


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.

 
 » References Top

1.Massano J, Bhatia KP. Clinical approach to Parkinson's disease: Features, diagnosis, and principles of management. Cold Spring Harb Perspect Med 2012;2:a008870.  Back to cited text no. 1
[PUBMED]    
2.Lesage S, Brice A. Parkinson's disease: From monogenic forms to genetic susceptibility factors. Hum Mol Genet 2009;18:R48-59.  Back to cited text no. 2
[PUBMED]    
3.Grossman MH, Emanuel BS, Budarf ML. Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.1q11.2. Genomics 1992;12:822-5.  Back to cited text no. 3
    
4.Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melén K, Julkunen I, et al. Kinetics of human soluble and membrane-bound catechol O-methyltransferase: A revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 1995;34:4202-10.  Back to cited text no. 4
    
5.Hoda F, Nicholl D, Bennett P, Arranz M, Aitchison KJ, al-Chalabi A, et al. No association between Parkinson's disease and low-activity alleles of catechol O-methyltransferase. Biochem Biophys Res Commun 1996;228:780-4.  Back to cited text no. 5
[PUBMED]    
6.Bialecka M, Kurzawski M, Klodowska-Duda G, Opala G, Tan EK, Drozdzik M. The association of functional catechol-O-methyltransferase haplotypes with risk of Parkinson's disease, levodopa treatment response, and complications. Pharmacogenet Genomics 2008;18:815-21.  Back to cited text no. 6
[PUBMED]    
7.Eerola J, Launes J, Hellström O, Tienari PJ. Apolipoprotein E (APOE), PARKIN and catechol-O-methyltransferase (COMT) genes and susceptibility to sporadic Parkinson's disease in Finland. Neurosci Lett 2002;330:296-8.  Back to cited text no. 7
    
8.Goudreau JL, Maraganore DM, Farrer MJ, Lesnick TG, Singleton AB, Bower JH, et al. Case-control study of dopamine transporter-1, monoamine oxidase-B, and catechol-O-methyl transferase polymorphisms in Parkinson's disease. Mov Disord 2002;17:1305-11.  Back to cited text no. 8
[PUBMED]    
9.Hernán MA, Checkoway H, O'Brien R, Costa-Mallen P, De Vivo I, Colditz GA, et al. MAOB intron 13 and COMT codon 158 polymorphisms, cigarette smoking, and the risk of PD. Neurology 2002;58:1381-7.  Back to cited text no. 9
    
10.Kalinderi K, Fidani L, Kourtesi G, Katsarou Z, Mioglou E, Bostantjopoulou S. No association of the Val158Met COMT polymorphism with Parkinson's disease in the Greek population. Eur J Neurol 2008;15:e83.  Back to cited text no. 10
    
11.Kunugi H, Nanko S, Ueki A, Otsuka E, Hattori M, Hoda F, et al. High and low activity alleles of catechol-O-methyltransferase gene: Ethnic difference and possible association with Parkinson's disease. Neurosci Lett 1997;221:202-4.  Back to cited text no. 11
    
12.Mizuta I, Mizuta E, Yamasaki S, Kuno S, Yasuda M, Tanaka C. Meta-analysis of polymorphism of the catechol-O-methyltransferase gene in relation to the etiology of Parkinson's disease in Japan. Mov Disord 2000;15:1013-4.  Back to cited text no. 12
    
13.Ming S, Zuolin L, Enxiang T, Biao C. Correlation between the genetic polymorphism of dopamine metabolic enzymes and the genetic susceptibility of Parkinson's disease. J Gerontol 2005;25:743-5.  Back to cited text no. 13
    
14.Syvänen AC, Tilgmann C, Rinne J, Ulmanen I. Genetic polymorphism of catechol-O-methyltransferase (COMT): Correlation of genotype with individual variation of S-COMT activity and comparison of the allele frequencies in the normal population and parkinsonian patients in Finland. Pharmacogenetics 1997;7:65-71.  Back to cited text no. 14
    
15.Watanabe M, Harada S, Nakamura T, Ohkoshi N, Yoshizawa K, Hayashi A, et al. Association between catechol-O-methyltransferase gene polymorphisms and wearing-off and dyskinesia in Parkinson's disease. Neuropsychobiology 2003;48:190-3.  Back to cited text no. 15
    
16.Wu RM, Cheng CW, Chen KH, Lu SL, Shan DE, Ho YF, et al. The COMT L allele modifies the association between MAOB polymorphism and PD in Taiwanese. Neurology 2001;56:375-82.  Back to cited text no. 16
    
17.Xu L, Hao YX, Xie HJ, Tang GM, Ren DP. Catecholamine-O- methyltransferase (COMT) gene polymorphism and the risk of Parkinson's disease in Shanghai Han population. Chin J Med Genet 2002;19:440-1.  Back to cited text no. 17
    
18.Xie T, Ho SL, Li LS, Ma OC. G/A1947 polymorphism in catechol-O-methyltransferase (COMT) gene in Parkinson's disease. Mov Disord 1997;12:426-7.  Back to cited text no. 18
    
19.Yoritaka A, Hattori N, Yoshino H, Mizuno Y. Catechol-O-methyltransferase genotype and susceptibility to Parkinson's disease in Japan. Short communication. J Neural Transm 1997;104:1313-7.  Back to cited text no. 19
    
20.Lee MS, Lyoo CH, Ulmanen I, Syvänen AC, Rinne JO. Genotypes of catechol-O-methyltransferase and response to levodopa treatment in patients with Parkinson›s disease. Neurosci Lett 2001;298:131-4.  Back to cited text no. 20
    
21.Lynch DR, Mozley PD, Sokol S, Maas NM, Balcer LJ, Siderowf AD. Lack of effect of polymorphisms in dopamine metabolism related genes on imaging of TRODAT-1 in striatum of asymptomatic volunteers and patients with Parkinson's disease. Mov Disord 2003;18:804-12.  Back to cited text no. 21
    
22.Kiyohara C, Miyake Y, Koyanagi M, Fujimoto T, Shirasawa S, Tanaka K, et al. Genetic polymorphisms involved in dopaminergic neurotransmission and risk for Parkinson's disease in a Japanese population. BMC Neurol 2011;11:89.  Back to cited text no. 22
    
23.Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM. Human catechol-O-methyltransferase pharmacogenetics: Description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996;6:243-50.  Back to cited text no. 23
    
24.Shield AJ, Thomae BA, Eckloff BW, Wieben ED, Weinshilboum RM. Human catechol O-methyltransferase genetic variation: Gene resequencing and functional characterization of variant allozymes. Mol Psychiatry 2004;9:151-60.  Back to cited text no. 24
    
25.Lee SG, Joo Y, Kim B, Chung S, Kim HL, Lee I, et al. Association of Ala72Ser polymorphism with COMT enzyme activity and the risk of schizophrenia in Koreans. Hum Genet 2005;116:319-28.  Back to cited text no. 25
    
26.Martínez MF, Martín XE, Alcelay LG, Flores JC, Valiente JM, Juanbeltz BI, et al. The COMT Val158 Met polymorphism as an associated risk factor for Alzheimer disease and mild cognitive impairment in APOE 4 carriers. BMC Neurosci 2009;10:125.  Back to cited text no. 26
    
27.Ozelius LJ, Senthil G, Saunders-Pullman R, Ohmann E, Deligtisch A, Tagliati M, et al. LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med 2006;354:424-5.  Back to cited text no. 27
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]

This article has been cited by
1 Roles of functional catechol-O-methyltransferase genotypes in Chinese patients with Parkinson’s disease
Yiwei Qian,Jiujiang Liu,Shaoqing Xu,Xiaodong Yang,Qin Xiao
Translational Neurodegeneration. 2017; 6(1)
[Pubmed] | [DOI]
2 Catechol-O-methyltransferase Val158Met polymorphism influences prefrontal executive function in early Parkinsonæs disease
Youwen Zhang,Shujun Feng,Kun Nie,Xin Zhao,Rong Gan,Limin Wang,Jiehao Zhao,Hongmei Tang,Liang Gao,Ruiming Zhu,Lijuan Wang,Yuhu Zhang
Journal of the Neurological Sciences. 2016; 369: 347
[Pubmed] | [DOI]
3 Asian perspectives on the recognition and management of levodopa ‘wearing-off’ in Parkinson’s disease
Roongroj Bhidayasiri,Nobutaka Hattori,Beomseok Jeon,Rou-Shayn Chen,Moon Keen Lee,Jawad A Bajwa,Vincent CT Mok,Baorong Zhang,Thamrin Syamsudin,Louis Chew Seng Tan,Roland Dominic G Jamora,Apichart Pisarnpong,Werner Poewe
Expert Review of Neurotherapeutics. 2015; 15(11): 1285
[Pubmed] | [DOI]
4 Dopaminergic denervation severity depends on COMT Val158Met polymorphism in Parkinsonæs disease
Julia Muellner,Iman Gharrad,Marie-Odile Habert,Aurélie Kas,Jean-Baptiste Martini,Florence Cormier-Dequaire,Khadija Tahiri,Marie Vidailhet,Niklaus Meier,Alexis Brice,Michael Schuepbach,Alain Mallet,Andreas Hartmann,Jean-Christophe Corvol
Parkinsonism & Related Disorders. 2015; 21(5): 471
[Pubmed] | [DOI]
5 Val158Met polymorphism of COMT gene and Parkinson’s disease risk in Asians
Lixue Chuan,Jie Gao,Yuying Lei,Raoxiang Wang,Lechun Lu,Xianyu Zhang
Neurological Sciences. 2015; 36(1): 109
[Pubmed] | [DOI]
6 COMT gene and risk for Parkinson’s disease
Félix J. Jiménez-Jiménez,Hortensia Alonso-Navarro,Elena García-Martín,José A.G. Agúndez
Pharmacogenetics and Genomics. 2014; 24(7): 331
[Pubmed] | [DOI]
7 COMT Val158Met and PPAR? Pro12Ala polymorphisms and susceptibility to Alzheimer’s disease: a meta-analysis
Young Ho Lee,Gwan Gyu Song
Neurological Sciences. 2014;
[Pubmed] | [DOI]
8 Sexual dimorphism in xenobiotic genetic variants-mediated risk for Parkinson’s disease
Nadella Kumudini,Addepally Uma,Shaik Mohammad Naushad,Rukmini Mridula,Rupam Borgohain,Vijay Kumar Kutala
Neurological Sciences. 2014;
[Pubmed] | [DOI]
9 Association of COMT Val158Met polymorphism with wearing-off susceptibility in Parkinson’s disease
Jianxing Liu,Pan Chen,Meihua Guo,Lechun Lu,Lihua Li
Neurological Sciences. 2014;
[Pubmed] | [DOI]



 

Top
Print this article  Email this article
   
Online since 20th March '04
Published by Wolters Kluwer - Medknow