Startseite Correlation between CTLA-4 gene rs221775A>G single nucleotide polymorphism and multiple sclerosis susceptibility. A meta-analysis
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Correlation between CTLA-4 gene rs221775A>G single nucleotide polymorphism and multiple sclerosis susceptibility. A meta-analysis

  • Xiao Haibing EMAIL logo , Cao Xu , Cai Jifu , Zeng Wenshuang , Li Ling , Cui Yuzhen und Hu Yanjun
Veröffentlicht/Copyright: 22. Juli 2016
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Open Medicine
Aus der Zeitschrift Open Medicine Band 11 Heft 1

Abstract

Objective

The aim of this meta-analysis was to undertake a meta-analysis to evaluate the correlation between cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene rs221775 A>G single nucleotide polymorphism and the susceptibility of multiple sclerosis (MS) susceptibility.

Method

Published manuscripts about CTLA-4 gene rs221775A>G single nucleotide polymorphism and multiple sclerosis susceptibility were searched in the computerized bibliographic searches of Pubmed Embase and China National Knowledge Infrastructure (CNKI). Potential studies were screened and data for 5025 MS patients and 4706 controls from 20 publications were included. The association between CTLA-4 gene rs221775A>G single nucleotide polymorphism and multiple sclerosis susceptibility were demonstrated by odds ratio (OR) and 95% confidence interval (95%CI).

Results

The pooled results showed no significant association between CTLA-4 gene rs221775A>G single nucleotide polymorphism and multiple sclerosis susceptibility for dominant genetic model [OR=1.02, 95%CI:0.90~1.05, (P=0.80)], homozygous genetic model [OR=0.85,95%CI:0.71 ~1.03,(P=0.10)] and recessive genetic model [OR=0.99,95% CI:0.89~1.10,(P=0.90)].

Conclusion

With current evidence, CTLA-4 gene rs221775A>G single nucleotide polymorphism had no association with the susceptibility of multiple sclerosis

Keywords: Multiple sclerosis; CTLA-4 gene; Susceptibility; Polymorphism; Meta-analysis

1 Introduction

Multiple sclerosis (MS) is a kind of demyelinating disease in which the insulating cover of nerve cells in the brain and spinal cord are damaged. And it was reported that MS is the most common diagnosized autoimmune disease which can affect the central nervous system. Clinical epidemology study estimated that about 2,300,000 subjects were affected by MS globally in the year of 2013, and about 20,000 people died from MS at the same year [1]. MS has the ability to reduce the communication of the central nervous system, which can lead to a range of signs and symptoms, including physical, mental, and sometimes psychiatric problems [2]. Generally, MS is not believed to be a hereditary disease, but some studies indicated that the genetic variations could have an association with the increasing risk of developing MS [3]. One of the related genes is cytotoxic T lymphocyte-associated antigen 4(CTLA-4), which is expressed on the surface of T cells and is critical in inhibiting T cell activation. Several studies have reported a significant correlation between CTLA-4 gene rs221775A>G single nucleotide polymorphism and multiple sclerosis susceptibility [4, 5]. However, other studies have not find a significant correlation [6-8]. Thus, we performed a meta-analysis by pooling all the available data related to CTLA-4 gene rs221775A>G single nucleotide polymorphism and multiple sclerosis susceptibility in order to further evaluted the corrlation.

2 Method

2.1 Publication search strategy

The open published studies about the CTLA-4 gene rs221775A>G single nucleotide polymorphism and multiple sclerosis susceptibility were searched in the databases of Pubmed Embase and China National Knowledge Infrastructure (CNKI). The case-control or cohort studies published in English or Chinese were all searched in the databases before Jan 2016. The search strategy and text words were: “cytotoxic T lymphocyte associated antigen/CTLA-4/CTLA4”, “multiple sclerosis/MS” or “polymorphism”. The references for the included papers were also screened to identify additional potential suitable studies which were not indexed in the pubmed or CNKI databases.

2.2 Inclusion and exclusion criteria

The inclusion criteria were as follows: (1) the study design was cases-cotrol or cohort; (2) the paper was published in English or Chinese; (3) the genotyping method is correct; (4) the frequency of AA, AG and GG nucleotide can be extracted from the original study. And the exclusion criteria were: (1) the study design type were review or case report; (2) studies with duplicate published datas; (3) Studies publised in other languages (not English or Chinese); (4) the data extracted from the original studies was not enough to calculate the ORs.

2.3 Data evaluation

Two reviewers (XIAO Haibing & CAO Xu) of this manuscript independently reviewed the papers and extracted the data according to the Cochrane Handbook. The general information such as first author, the paper publication year, the country of the study performed, and the race of the included subjects for each of the included paper were extacted. The frequency of AA, AG and GG nucleotide for the include 20 studies were canrefully extracted and corss checked, which was used to calculated the pooled ORs. If disagreements were encountered, the discussion was made and a third reviewer was consulted.

2.4 Statistical analysis

Stata/SE 11.0（StataCorp LP, http://www.stata.com were used for statistical analysis. The correlation between CTLA-4 gene rs221775A>G single nucleotide polymorphism and multiple sclerosis susceptibility was demonstrated by odds ratio (OR) and its 95% confidence interval (95%CI). Statistical heterogeneity among studies was evaluated by I2 [9]. If significant heterogeneity was found (I2＞50%), the random-effect method (Dersimonian-Laird method) was used to pool the data. Inversely, fixed-effect method was applied. The publication bias was detected by Begg’s funnelplot.

3 Results

3.1 General information of the included studies

Through searching the databases, 86 related publication were initial identified. 66 studies were excluded after reviewing the complete text. Overall, we included twenty published articles in this meta-analysis with 5025 MS patients and 4706 controls. For the inlcuded 20 open published studies, 14 articles included the subjects with race of Caucasus, 3 with Arab, 1 with mixed, 1 with Asian and 1 with Australoid. The publication year ranged form 1999 to 2011. All papers were published in English. General information of the included 20 papers are demonstrated in Table 1.

Table 1

General information for the included studies

AuthorsYearCountryRaceNoCaseControl
MSControlAAAGGGAAAGGG
Ligers etal[4]1999SwedenCaucasus378237117188738312331
Rasmussen(1) et al[6]2001DenmarkCaucasus84125283917356822
Rasmussen(2) et al[6]2001DenmarkCaucasus42864231573445
Andreevskii et al[7]2002RussiaCaucasus1682095185326810437
Masterman et al[8]2002SwedenCaucasus374290120188668213969
Maurer et al[5]2002GermanyCaucasus33015213215741666917
Bocko et al[10]2003PolandCaucasus102101315714355313
Kantarci et al[11]2003USAMixed1202354559158911135
van Veen et al[12]2003NetherlandsCaucasus51418121522970728524
Bilinska et al[13]2004PolandCaucasus152154478025508420
Teutsch et al[14]2004AustraliaCaucasus102152305418646127
Fukazawa et al[15]2005JapanAsian133156236941296661
Lorentzen et al[16]2005NorwayCaucasus5135091642519816824992
Malferrari etal [17]2005ItalyCaucasus9510440469375413
Dincic et al[18]2006MontenegroCaucasus16210296561041529
Heggarty et eal[19]2007EnglandCaucasus33015812914853468428
Greve(1) etal [20]2008PolandCaucasus180171599625499032
Greve(2) etal[20]2008GermanyCaucasus20046475903517821670
Greve(3) etal[20]2008HungaryCaucasus19391649633324811
Wray et al[21]2008AustraliaAustraloid19822465111228610731
Yousefipour et al [1]2009IranArab1531907956181175914
Heidari et al[22]2010IranArab135135426924387423
Cizmarevic et al[23]2011IranArab3674801511655119822161

3.2 Dominant genetic model (GG+AG vs AA)

For the dominant genetic model (GG+AG vs AA), significant heterogeneity across the included twenty article existed (I2=82.5%, P=0.00). The OR was pooled by random effect model. The pooled OR was 1.06 and 95% confidence interval was 0.86～1.30 wich indicated that there was no significant association between CTLA-4 gene rs221775 A>G single nucleotide polymorphism and multiple sclerosis susceptibility in dominant genetic model (GG+AG vs AA (Figure 1). The begg’s funnel plot indicated no significant publication bias (Figure 2).

Figure 1 The forest plot of OR for CTLA-4 gene rs221775 A>G single nucleotide polymorphism and multiple sclerosis susceptibility under dominant model (GG+AG vs AA).
Figure 1

The forest plot of OR for CTLA-4 gene rs221775 A>G single nucleotide polymorphism and multiple sclerosis susceptibility under dominant model (GG+AG vs AA).

Figure 2 The Begg’s funnel plots showe no significant publication bias under dominant model (GG+AG vs AA)
Figure 2

The Begg’s funnel plots showe no significant publication bias under dominant model (GG+AG vs AA)

3.3 Homozygous genetic model (GG vs AA)

For the homozygous genetic model (GG vs AA), no significant heterogeneity across the included 20 articles were found (I2=0.80%, P=0.45). So, the OR was pooled by fixed effect model. The pooled OR showed no significant correlation between CTLA-4 gene rs221775 A>G single nucleotide polymorphism and multiple sclerosis susceptibility was found in homozygous genetic model (GG vs AA) (Figure 3). The pulication bias was evaluated by funnel plot, which indicated no significant publication bias (Figure 4).

Figure 3 The forest plot of OR for CTLA-4 gene rs221775 A>G single nucleotide polymorphism and multiple sclerosis susceptibility under homozygous genetic model (GG vs AA).
Figure 3

The forest plot of OR for CTLA-4 gene rs221775 A>G single nucleotide polymorphism and multiple sclerosis susceptibility under homozygous genetic model (GG vs AA).

Figure 4 The Begg’s funnel plots showe no significant publication bias homozygous genetic model (GG vs AA).
Figure 4

The Begg’s funnel plots showe no significant publication bias homozygous genetic model (GG vs AA).

3.4 Recessive genetic model (GG vs AG+AA)

For the recessive genetic model (GG vs AG+AA), the heterogeneity across the studies were assesed by I2 which showed no significant heterogeneity across the studies (I2§=81.2%, P=0.45). We pooled the data by fixed effect mode. The pooled the results indicated no statistical association between CTLA-4 gene rs221775 A>G single nucleotide polymorphism and multiple sclerosis susceptibility in recessive genetic model (GG vs AG+AA) (Figure 5). And begg’s funnel plot was symmetric which indicated no significant publication bias (Figure 6).

Figure 5 The forest plot of OR for CTLA-4 gene rs221775 A>G single nucleotide polymorphism and multiple sclerosis susceptibility under recessive genetic model (GG vs AG+AA)
Figure 5

The forest plot of OR for CTLA-4 gene rs221775 A>G single nucleotide polymorphism and multiple sclerosis susceptibility under recessive genetic model (GG vs AG+AA)

Figure 6 The Begg’s funnel plots showe no significant publication bias under recessive genetic model(GG vs AG+AA)
Figure 6

The Begg’s funnel plots showe no significant publication bias under recessive genetic model(GG vs AG+AA)

4 Discussion

Generally, the causes for MS is unclear. However, it is believed that it could be the result of a combination of genetic and environmental factorial influences (such as infectious agents) [24]. Results of publised studies have demonstrated that some genetic variations can increase the risk of developing MS [11]. These genes seem to be expresed higher in microglial cells than expected by chance. Cytotoxic T-lymphocyte-associated protein 4 gene was one of these genes that was positive expressed in activated T lymph cells and played an important role in inhibiting the function of T lymph cell [25].

CTLA-4, also known as CD152 (cluster of differentiation 152), is a protein receptor that functions as an immune checkpoint, downregulates the immune system. Animal experiment showed that disruption of CTLA-4 leads to fatal lymphoproliferative disorder, which could result in a widespread autoimmunity in mice [26]. Recently, seveal studies have found the cytotoxic T-lymphocyte-associated protein 4(CTLA-4) gene rs221775A>G single nucleotide polymorphism to be associated with the susceptibility of multiple sclerosis [4, 19]. Heggarty and his colleges [19] discussed the relationship between CTLA4 gene polymorphisms and multiple sclerosis risk in Northern Ireland. They found that people with A allele and AA genotype of rs221775 had more risk of developing MS (OR=1.36, P<0.05 for A allele and OR=1.81, P<0.05 for AA genotype).

Significnat correlation between CTLA-4 gene rs221775A>G single nucleotide polymorphism and MS risk was demonstrated in their study. Kantarci et al [11] also found that CTLA4 was associated with susceptibility to multiple sclerosis. They performed a population-based sample of 122 sporadic patients with MS and 244 age-, gender- and ethnicity-matched controls, and by linkage and family-based association methods in 395 individuals from 59 American multiplex pedigrees with 141 affected individuals. They found a strong association with age at onset, disease course and severity. Moreover they found that CTLA-4 was associated with the susceptibility to MS.

On the other hand, Greve et al [20] found no association between CTLA4 polymorphism and MS susceptibility in patients from Germany, Hungary and Poland. Thus, the results for CTLA4 polymorphism and MS risk is not conclusive within published articles. The current meta-analysis pooling of publised data were preformed in order to further evaluated the correlation between CTLA4 gene polymorphisms and multiple sclerosis. We included 20 studies involving 5025 MS patients and 4706 controls. No significant correlation between CTLA4 polymorphism and MS in dominant genetic model (GG+AG vs AA), homozygous genetic model (GG vs AA) or recessive genetic model(GG vs AG+AA) genetic model were found.

There are several limitations with the present meta-analysis to be considered. Firstly, heterogeneity existed in dominant genetic model (GG+AG vs AA), which could reduce the statistical power for pooling the data. Secondly, only paper published in English or Chinese had been screened in the databases and include. Thirdly, MS is a complex diseases, which is the result of the combined actions of multiple susceptibility genes and one or more environmental factors, and only the association between one single nucleotide polymorphism for one gene was evaluated which may not be enough.

Funding from Shenzhen Science, Technology and Innovation Committee. No. JCYJ20150331142757395

Conflict of interest statement

Authors state no conflict of interest.

Xiao Haibing, Neurology, Internal Medicine, The University of Hong Kong-Shenzhen Hospital. No 1, Haiyuan 1st Road, Futian District, Shenzhen, Guangdong, PR China. 518053

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Received: 2016-3-29
Accepted: 2016-6-13
Published Online: 2016-7-22
Published in Print: 2016-1-1

© 2016 Xiao Haibing et al.

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

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  151. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  152. Professional dental and oral surgery liability in Italy: a comparative analysis of the insurance products offered to health workers
  153. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  154. Informed consent in robotic surgery: quality of information and patient perception
  155. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  156. Malfunctions of robotic system in surgery: role and responsibility of surgeon in legal point of view
  157. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  158. Medicolegal implications of surgical errors and complications in neck surgery: A review based on the Italian current legislation
  159. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  160. Iatrogenic splenic injury: review of the literature and medico-legal issues
  161. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  162. Donation of the body for scientific purposes in Italy: ethical and medico-legal considerations
  163. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  164. Cosmetic surgery: medicolegal considerations
  165. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  166. Voluntary termination of pregnancy (medical or surgical abortion): forensic medicine issues
  167. Review Article
  168. Role of Laparoscopic Splenectomy in Elderly Immune Thrombocytopenia
  169. Review Article
  170. Endoscopic diagnosis and treatment of neuroendocrine tumors of the digestive system
  171. Review Article
  172. Efficacy and safety of splenectomy in adult autoimmune hemolytic anemia
  173. Research Article
  174. Relationship between gastroesophageal reflux disease and Ph nose and salivary: proposal of a simple method outpatient in patients adults
  175. Case Report
  176. Idiopathic pleural panniculitis with recurrent pleural effusion not associated with Weber-Christian disease
  177. Research Article
  178. Morbid Obesity: treatment with Bioenterics Intragastric Balloon (BIB), psychological and nursing care: our experience
  179. Research Article
  180. Learning curve for endorectal ultrasound in young and elderly: lights and shades
  181. Case Report
  182. Uncommon primary hydatid cyst occupying the adrenal gland space, treated with laparoscopic surgical approach in an old patient
  183. Research Article
  184. Distraction techniques for face and smile aesthetic preventing ageing decay
  185. Research Article
  186. Preoperative high-intensity training in frail old patients undergoing pulmonary resection for NSCLC
  187. Review Article
  188. Descending necrotizing mediastinitis in the elderly patients
  189. Research Article
  190. Prophylactic GSV surgery in elderly candidates for hip or knee arthroplasty
  191. Research Article
  192. Diagnostic yield and safety of C-TBNA in elderly patients with lung cancer
  193. Research Article
  194. The learning curve of laparoscopic holecystectomy in general surgery resident training: old age of the patient may be a risk factor?
  195. Research Article
  196. Self-gripping mesh versus fibrin glue fixation in laparoscopic inguinal hernia repair: a randomized prospective clinical trial in young and elderly patients
  197. Research Article
  198. Anal sphincter dysfunction in multiple sclerosis: an observation manometric study
https://doi.org/10.1515/med-2016-0052
Schlagwörter für diesen Artikel
Multiple sclerosis; CTLA-4 gene; Susceptibility; Polymorphism; Meta-analysis
Creative Commons
BY-NC-ND 3.0

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  127. Special Issue on Italian Society for the Study of Vascular Anomalies
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  129. Special Issue on Italian Society for the Study of Vascular Anomalies
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  131. Special Issue on Italian Society for the Study of Vascular Anomalies
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  133. Special Issue on Italian Society for the Study of Vascular Anomalies
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  135. Special Issue on Italian Society for the Study of Vascular Anomalies
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  137. Special Issue on Italian Society for the Study of Vascular Anomalies
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  139. Special Issue on Italian Society for the Study of Vascular Anomalies
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  141. Special Issue on Italian Society for the Study of Vascular Anomalies
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  143. Special Issue on Italian Society for the Study of Vascular Anomalies
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  145. Special Issue on Italian Society for the Study of Vascular Anomalies
  146. Celiac axis compression syndrome: laparoscopic approach in a strange case of chronic abdominal pain in 71 years old man
  147. Special Issue on Italian Society for the Study of Vascular Anomalies
  148. A rare case of persistent hypoglossal artery associated with contralateral proximal subclavian stenosis
  149. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  150. Contralateral risk reducing mastectomy in Non-BRCA-Mutated patients
  151. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  152. Professional dental and oral surgery liability in Italy: a comparative analysis of the insurance products offered to health workers
  153. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  154. Informed consent in robotic surgery: quality of information and patient perception
  155. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  156. Malfunctions of robotic system in surgery: role and responsibility of surgeon in legal point of view
  157. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  158. Medicolegal implications of surgical errors and complications in neck surgery: A review based on the Italian current legislation
  159. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  160. Iatrogenic splenic injury: review of the literature and medico-legal issues
  161. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  162. Donation of the body for scientific purposes in Italy: ethical and medico-legal considerations
  163. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  164. Cosmetic surgery: medicolegal considerations
  165. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  166. Voluntary termination of pregnancy (medical or surgical abortion): forensic medicine issues
  167. Review Article
  168. Role of Laparoscopic Splenectomy in Elderly Immune Thrombocytopenia
  169. Review Article
  170. Endoscopic diagnosis and treatment of neuroendocrine tumors of the digestive system
  171. Review Article
  172. Efficacy and safety of splenectomy in adult autoimmune hemolytic anemia
  173. Research Article
  174. Relationship between gastroesophageal reflux disease and Ph nose and salivary: proposal of a simple method outpatient in patients adults
  175. Case Report
  176. Idiopathic pleural panniculitis with recurrent pleural effusion not associated with Weber-Christian disease
  177. Research Article
  178. Morbid Obesity: treatment with Bioenterics Intragastric Balloon (BIB), psychological and nursing care: our experience
  179. Research Article
  180. Learning curve for endorectal ultrasound in young and elderly: lights and shades
  181. Case Report
  182. Uncommon primary hydatid cyst occupying the adrenal gland space, treated with laparoscopic surgical approach in an old patient
  183. Research Article
  184. Distraction techniques for face and smile aesthetic preventing ageing decay
  185. Research Article
  186. Preoperative high-intensity training in frail old patients undergoing pulmonary resection for NSCLC
  187. Review Article
  188. Descending necrotizing mediastinitis in the elderly patients
  189. Research Article
  190. Prophylactic GSV surgery in elderly candidates for hip or knee arthroplasty
  191. Research Article
  192. Diagnostic yield and safety of C-TBNA in elderly patients with lung cancer
  193. Research Article
  194. The learning curve of laparoscopic holecystectomy in general surgery resident training: old age of the patient may be a risk factor?
  195. Research Article
  196. Self-gripping mesh versus fibrin glue fixation in laparoscopic inguinal hernia repair: a randomized prospective clinical trial in young and elderly patients
  197. Research Article
  198. Anal sphincter dysfunction in multiple sclerosis: an observation manometric study
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