Abstract
Backround
The association between PTPN22 R620W polymorphism and risk of myasthenia gravis (MG) remains controversial. Therefore, we did this meta-analysis to investigate this association.
Material/Methods
We did a comprehensive search in PubMed, Medline, Embase, CNKI (China National Knowledge Infrastructure), and Wanfang electronic databases to retrieve relevant articles. The overall effect was measured by odds ratios (ORs) with its 95% confidence intervals (CIs). Statistical analyses were conducted with STATA software.
Results
Overall, a total of 7 case-control studies with 2802 cases and 3730 controls were finally included in this review. PTPN22 R620W polymorphism was significantly associated with an increased risk of MG (OR=1.57; 95% CI, 1.34–1.82; I2=31%). In the subgroup analysis, thymoma patients were significantly associated with risk of MG (OR=1.59; 95% CI, 1.28–1.98; I2=0%). However, non-thymoma patients with this polymorphism did not have increased MG risk (OR=1.36; 95% CI, 0.86–2.15; I2=77%). In addition, PTPN22 R620W polymorphism showed increased early-onset myasthenia gravis (EOMG) risk (OR=2.38; 95% CI, 1.52–3.71; I2=0%).
Conclusions
This meta-analysis shows a significant association between PTPN22 R620W polymorphism and MG risk.
MeSH Keywords: Genetic Association Studies, Meta-Analysis, Myasthenia Gravis
Background
The annual incidence of myasthenia gravis (MG) is reported to be 0.25–4 patients per 100 000 population, with the first peak of onset around the second and third decades of life and the second peak around the fifth and sixth decades [1]. In most cases, it is caused by pathogenic autoantibodies directed toward the skeletal muscle acetylcholine receptor (AChR), but in others, non-AChR components of the postsynaptic muscle endplate, such as the muscle-specific receptor tyrosine kinase (MUSK), might serve as targets of autoimmune attack [2]. The exact mechanism of the autoimmune response in MG is unknown [3–5]. However, genetic factors might play an important role in the development of MG [6,7].
Human leukocyte antigen (HLA) loci are associated with all autoimmune diseases and are the strongest genetic factors for individual predisposition [8]. Of the non-HLA susceptibility genes, variants of protein tyrosine phosphatase non-receptor type (PTPN22) show the strongest associations with autoimmune diseases. A SNP in PTPN22 has been reported to be associated with type 1 diabetes (T1DM) [9], rheumatoid arthritis (RA) [10], systemic lupus erythematosus (SLE) [11], Hashimoto’s thyroiditis [12].
In addition, some studies also suggested that PTPN22 R620W polymorphism was associated with MG risk [13–19]. However, the association between this polymorphism and the risk of MG was controversial and inconclusive. Thus, we did a meta-analysis to determine if this polymorphism could influence MG risk.
Material and Methods
Publication search
We did a comprehensive search in PubMed, Medline, Embase, CNKI (China National Knowledge Infrastructure) and Wanfang to retrieve relevant articles. We retrieved the relevant articles using the following terms: “myasthenia gravis”, “PTPN22”, and “polymorphism or variant or mutation” as well as their combinations. We searched the references of retrieved articles with no language restriction.
Inclusion and exclusion criteria
The studies must meet the following criteria: 1) the paper should be case-control studies; 2) evaluating the contribution of PTPN22 R620W polymorphism with MG risk; 3) genotype distributions in the cases and controls were available to extract, and the results presented in odds ratio (ORs) with its 95% confidence interval (CI); and 4) for a certain polymorphism, genotype distribution in the controls must be in Hardy-Weinberg equilibrium (HWE).
Data extraction
Two investigators independently estimated the extracted data of the included studies to reach a consensus. The following information was extracted from each article: first author, year of publication, country, ethnicity, age, gender, type of MG, sample size.
Quality assessment
The Newcastle-Ottawa scale (NOS) for case-control studies was used to assess the methodological quality of every included study. Three parameters were examined in the NOS: selection, comparability, and exposure. The highest study quality was nine stars with a maximum of four stars for selection, two stars for comparability, and three stars for exposure in the NOS. The ultimate score of 6 stars or more was regarded as high-quality.
Statistical analysis
The overall effect was measured by ORs with its 95% CI. The significance of the pooled ORs was determined by the Z test with a P value less than 0.05 considering statistically significant. The per-allele model was examined to assess this association. Between-studies heterogeneity was assessed by the I2 test and the Q-statistic test. The random-effect model was used. The publication bias was estimated by funnel plot. We did a sensitivity analysis. Statistical analyses were conducted in STATA version 11.0 (Stata Corporation, College station, TX, USA). All the tests were two-sided. Bonferroni correction was applied.
Results
Study characteristics
Of the 46 references, 3 records excluded for duplication and 43 articles were judged potentially relevant. Following titles and abstracts screened for relevance, 36 full-text articles comprehensively assessed against inclusion criteria. A total of 7 case-control studies with 2802 cases and 3730 controls were finally included in this review. Figure 1 showed the study flow. All of the studies were performed using Caucasians. Table 1 shows the main characteristics of studies for meta-analysis. All the included studies were high quality studies.
Figure 1.
Flow chat of study selection process.
Table 1.
Characteristics of the included studies.
| First author | Year | Country | Ethnicity | Age | Gender | Type of MG | Total cases (n) | Total controls (n) | Hardy-Weinberg equilibrium | Quality Score |
|---|---|---|---|---|---|---|---|---|---|---|
| Vandiedonck | 2006 | France | Caucasian | 33 | Mixed | Mixed | 470 | 296 | Yes | 7 |
| Lefvert | 2008 | Sweden | Caucasian | NA | Mixed | Mixed | 409 | 1557 | Yes | 9 |
| Chuang | 2009 | Germany | Caucasian | 27 | Mixed | EOMG | 129 | 172 | Yes | 7 |
| Greve 1 | 2009 | Germany | Caucasian | NA | Mixed | Mixed | 134 | 199 | Yes | 8 |
| Greve 2 | 2009 | Hungary | Caucasian | NA | Mixed | Mixed | 148 | 180 | Yes | 8 |
| Gregersen | 2012 | France | Caucasian | 45 | Mixed | EOMG | 740 | 649 | Yes | 9 |
| Provenzano | 2012 | Italy | Caucasian | 40 | Mixed | Mixed | 356 | 384 | Yes | 8 |
| Kaya | 2014 | Turkey | Caucasian | 50 | Mixed | Mixed | 416 | 293 | Yes | 8 |
EOMG – early-onset myasthenia gravis.
Results of meta-analysis
The results are summarized in Table 2. PTPN22 R620W polymorphism was significantly associated with the risk of MG (OR=1.57; 95% CI, 1.34–1.82; I2=31%; Figure 2). In addition, thymoma patients was significantly associated with risk of MG (OR=1.59; 95% CI, 1.28–1.98; I2=0%). However, non-thymoma patients with this polymorphism did not have increased MG risk (OR=1.36; 95% CI, 0.86–2.15; I2=77%). Furthermore, PTPN22 R620W polymorphism showed increased early-onset myasthenia gravis (EOMG) risk (OR=2.38; 95% CI, 1.52–3.71; I2=0%). The sensitivity analysis suggested that the corresponding pooled ORs were not materially altered (data not shown).
Table 2.
Results of meta-analysis and subgroup analyses.
| Test of association | Heterogeneity | ||||||
|---|---|---|---|---|---|---|---|
| OR (95% CI) | Z | P value | Model | χ2 | P balue | I2 (%) | |
| Overall | 1.57 (1.34–1.82) | 5.74 | <0.00001 | R | 10.08 | 0.18 | 31 |
| Thymoma | 1.59 (1.28–1.98) | 4.15 | <0.0001 | R | 4.80 | 0.44 | 0 |
| Nonthymoma | 1.36 (0.86–2.15) | 1.31 | 0.19 | R | 8.51 | 0.01 | 77 |
| EOMG | 2.38 (1.52–3.71) | 3.82 | 0.001 | R | 0.01 | 0.93 | 0 |
R – random-effects model; EOMG – early-onset myasthenia gravis.
Figure 2.
Meta-analysis for the association between PTPN22 R620W polymorphism and MG risk.
The shape of the funnel plot showed symmetry (Figure 3). Egger’s test also found no evidence of publication bias (P=0.865).
Figure 3.
Funnel plot for the association between PTPN22 R620W polymorphism and MG risk.
Discussion
MG is an acquired organ-specific autoimmune disease, characterized by fluctuating weakness and fatigability of voluntary muscles due to the impairment of the neuromuscular transmission caused by autoantibodies. There is an urgent need to look for biomarkers evaluating the severity of the disease, predicting the prognosis of patients, and targeting the pathogenic genes. The present meta-analysis including 7 studies evaluated the association between PTPN22 R620W polymorphism and MG risk. We found that individuals with the PTPN22 R620W polymorphism showed an increased risk of MG in the overall population. This result suggested that PTPN22 R620W polymorphism may be a risk factor of MG. Furthermore, we found that PTPN22 R620W polymorphism might also be a risk factor of EOMG. In the subgroup analysis, thymoma patients with PTPN22 R620W polymorphism were significantly associated with risk of MG.
Previous study has reported the function of PTPN22 R620W polymorphism in Jurkat cell transfectants [20]. Vang and coworkers investigated effects of R620 versus W620 in cell stimulation with anti-CD3 and anti-CD28 [21]. They found that mutant phosphatase inhibited NFAT/AP1 more efficient with W620 variant than R620 variant. Thus, they suggested that W620 variant predisposed to MG because W620 variant may suppress T cell antigen receptor (TCR) signaling more potently during thymic development.
Several limitations should be addressed. Firstly, the subgroups may have a relatively lower power based on a small number of studies. Secondly, a more precise analysis should be conducted if individual information including other covariates such as age, sex and smoking condition becomes available. Thirdly, the gene-gene interaction is important for the development of complex diseases including MG.
Conclusions
This meta-analysis suggested a significant association between PTPN22 R620W polymorphism and MG risk.
Footnotes
Source of support: Departmental sources
Disclosure of conflict of interest
None.
References
- 1.Burns TM. History of outcome measures for myasthenia gravis. Muscle Nerve. 2010;42:5–13. doi: 10.1002/mus.21713. [DOI] [PubMed] [Google Scholar]
- 2.Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol. 2009;8:475–90. doi: 10.1016/S1474-4422(09)70063-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Olate S, Muñoz D, Neumann S, et al. A descriptive study of the oral status in subjects with Sjögren’s syndrome. Int J Clin Exp Med. 2014;7:1140–44. [PMC free article] [PubMed] [Google Scholar]
- 4.Wahono CS, Rusmini H, Soelistyoningsih D, et al. Effects of 1,25(OH)2D3 in immune response regulation of systemic lupus rithematosus (SLE) patient with hypovitamin D. Int J Clin Exp Med. 2014;7:22–31. [PMC free article] [PubMed] [Google Scholar]
- 5.Yuksel S, Pancar Yuksel E, et al. Abnormal nail fold capillaroscopic findings in patients with coronary slow flow phenomenon. Int J Clin Exp Med. 2014;7:1052–58. [PMC free article] [PubMed] [Google Scholar]
- 6.Deitiker PR, Oshima M, Smith RG, et al. Association with HLA DQ of early onset myasthenia gravis in Southeast Texas region of the United States. Int J Immunogenet. 2011;38:55–62. doi: 10.1111/j.1744-313X.2010.00979.x. [DOI] [PubMed] [Google Scholar]
- 7.Nikolic AV, Andric ZP, Simonovic RB, et al. High frequency of DQB1*05 and absolute absence of DRB1*13 in muscle-specific tyrosine kinase positive myasthenia gravis. Eur J Neurol. 2015;22(1):59–63. doi: 10.1111/ene.12525. [DOI] [PubMed] [Google Scholar]
- 8.Fernando MM, Stevens CR, Walsh EC, et al. Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet. 2008;4:e1000024. doi: 10.1371/journal.pgen.1000024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Douroudis K, Prans E, Haller K, et al. Protein tyrosine phosphatase non-receptor type 22 gene variants at position 1858 are associated with type 1 and type 2 diabetes in Estonian population. Tissue Antigens. 2008;72:425–30. doi: 10.1111/j.1399-0039.2008.01115.x. [DOI] [PubMed] [Google Scholar]
- 10.Wesoly J, van der Helm-van Mil AH, Toes RE, et al. Association of the PTPN22 C1858T single-nucleotide polymorphism with rheumatoid arthritis phenotypes in an inception cohort. Arthritis Rheum. 2005;52:2948–50. doi: 10.1002/art.21294. [DOI] [PubMed] [Google Scholar]
- 11.Lea WW, Lee YH. The association between the PTPN22 C1858T polymorphism and systemic lupus erythematosus: a meta-analysis update. Lupus. 2011;20:51–57. doi: 10.1177/0961203310381774. [DOI] [PubMed] [Google Scholar]
- 12.Criswell LA, Pfeiffer KA, Lum RF, et al. Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet. 2005;76:561–71. doi: 10.1086/429096. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Vandiedonck C, Capdevielle C, Giraud M, et al. Association of the PTPN22*R620W polymorphism with autoimmune myasthenia gravis. Ann Neurol. 2006;59:404–7. doi: 10.1002/ana.20751. [DOI] [PubMed] [Google Scholar]
- 14.Greve B, Hoffmann P, Illes Z, et al. The autoimmunity-related polymorphism PTPN22 1858C/T is associated with anti-titin antibody-positive myasthenia gravis. Hum Immunol. 2009;70:540–42. doi: 10.1016/j.humimm.2009.04.027. [DOI] [PubMed] [Google Scholar]
- 15.Gregersen PK, Kosoy R, Lee AT, et al. Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08. Ann Neurol. 2012;72:927–35. doi: 10.1002/ana.23691. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Chuang WY, Ströbel P, Belharazem D, et al. The PTPN22gain-of-function+1858T(+) genotypes correlate with low IL-2 expression in thymomas and predispose to myasthenia gravis. Genes Immun. 2009;10:667–72. doi: 10.1038/gene.2009.64. [DOI] [PubMed] [Google Scholar]
- 17.Kaya GA, Coşkun AN, Yılmaz V, et al. The association of PTPN22 R620W polymorphism is stronger with late-onset AChR-myasthenia gravis in Turkey. PLoS One. 2014;9:e104760. doi: 10.1371/journal.pone.0104760. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Provenzano C, Ricciardi R, Scuderi F, et al. PTPN22 and myasthenia gravis: replication in an Italian population and meta-analysis of literature data. Neuromuscul Disord. 2012;22:131–38. doi: 10.1016/j.nmd.2011.09.003. [DOI] [PubMed] [Google Scholar]
- 19.Lefvert AK, Zhao Y, Ramanujam R, et al. PTPN22 R620W promotes production of anti-AChR autoantibodies and IL-2 in myasthenia gravis. J Neuroimmunol. 2008;197:110–13. doi: 10.1016/j.jneuroim.2008.04.004. [DOI] [PubMed] [Google Scholar]
- 20.Zikherman J, Hermiston M, Steiner D, et al. PTPN22 deficiency cooperates with the CD45 E613R allele to break tolerance on a non-autoimmune background. J Immunol. 2009;182:4093–106. doi: 10.4049/jimmunol.0803317. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Vang T, Congia M, Macis MD, et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet. 2005;37(12):1317–19. doi: 10.1038/ng1673. [DOI] [PubMed] [Google Scholar]