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No Association of PTPN22 Polymorphisms with Susceptibility to Ocular Behcet's Disease in Two Chinese Han Populations

  • Qi Zhang,

    Affiliation Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China

  • Shengping Hou,

    Affiliation Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China

  • Zhengxuan Jiang,

    Affiliation Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China

  • Liping Du,

    Affiliation Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China

  • Fuzhen Li,

    Affiliation Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China

  • Xiang Xiao,

    Affiliation Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China

  • Aize Kijlstra,

    Affiliation Department of Ophthalmology, Eye Research Institute Maastricht, University Hospital Maastricht, Maastricht, The Netherlands

  • Peizeng Yang

    peizengycmu@126.com

    Affiliation Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China

No Association of PTPN22 Polymorphisms with Susceptibility to Ocular Behcet's Disease in Two Chinese Han Populations

  • Qi Zhang, 
  • Shengping Hou, 
  • Zhengxuan Jiang, 
  • Liping Du, 
  • Fuzhen Li, 
  • Xiang Xiao, 
  • Aize Kijlstra, 
  • Peizeng Yang
PLOS
x

Abstract

Background

Behcet's disease is known as a recurrent, multisystem inflammation and immune-related disease. Protein tyrosine phosphatase non-receptor 22 (PTPN22) is a key negative regulator of T lymphocytes and polymorphisms of the PTPN22 gene have been shown to be associated with various immune-related diseases. The present study was performed to assess the association between PTPN22 polymorphisms and Behcet's disease in two Chinese Han populations.

Methodology/Principal Findings

A total of 516 patients with ocular Behcet's disease and 690 healthy controls from two Chinese Han populations were genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method for three single nucleotide polymorphisms (SNPs). Hardy-Weinberg equilibrium was tested using the χ2 test. Genotype frequencies were estimated through direct counting. Allele and genotype frequencies were compared between patients and controls using logistic regression analysis. The results revealed that there was no association between the tested three PTPN22 SNPs (rs2488457, rs1310182 and rs3789604) and ocular Behcet's disease (p>0.05). Categorization analysis according to the clinical features did not show any association of these three polymorphisms with these parameters (p>0.05).

Conclusions/Significance

The investigated PTPN22 gene polymorphisms (rs2488457, rs1310182 and rs3789604) were not associated with ocular Behcet's disease in two Chinese Han populations, and showed that it may be different from other classical autoimmune diseases. More studies are needed to confirm these findings for Behcet's disease in other ethnic backgrounds.

Introduction

Behcet's disease (BD) is known as a multisystem inflammatory disorder of unknown etiology. It is characterized by recurrent attacks of uveitis, oral ulceration, genital ulceration, skin lesions, arthritis, and vascular inflammation [1]. It is curently recognized as an immune-related disease presenting with signs of immune hyper-reactivity mainly affecting elements of the innate immune system. Although the precise triggering factors for BD are still unclear, complex mechanisms including genetic, environmental and immunologic, are presumed to be involved [2][5]. Genetic susceptibility to BD has been investigated in different populations throughout the world. Human leukocyte antigen (HLA)-B51 is thought to be the most strongly associated genetic factor predisposing to BD. The contribution of HLA-B51 to the genetic risk of BD has however been estimated to be less than 20%. Therefore study on non-HLA genes, especially related to the immune response and inflammation is of great importance. Several immune relevant genes, such as the IL-23 receptor gene, IL-10 gene and SUMO4 gene, have been revealed to be risk factors for BD [6][9].

The protein tyrosine phosphatase non-receptor 22 (PTPN22) gene maps to chromosome 1p13.3-p13.1, and encodes the lymphoid-specific phosphatase known as Lyp, which contains a catalytic N-terminal domain and a non-catalytic C-terminus composed of four proline-rich domains. Lyp is an important down-regulator of T-cell activation through interacting with protein tyrosine kinase (Csk) and inhibiting signaling pathways mediated by the T-cell receptor (TCR) [10]. Several studies have revealed that the nucleotide diversity of PTPN22 could trigger the immune and inflammation response by decreasing the affinity between Lyp and Csk, thereby inhibiting the TCR signaling pathway [11][13]. PTPN22 has been shown to be associated with susceptibility to a number of immune related-diseases, such as type 1 diabetes (T1D), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) [14][16].

Earlier studies in a Turkish population with BD analyzed the rs2476601 genotype of the PTPN22 gene and concluded that this polymorphism had a limited (protective) role in disease pathogenesis [17]. A similar study including UK and Middle-East patients with BD showed a protective effect of the T1858 allele in the Middle East patients but not in the UK group [18]. As yet, in Chinese Han populations, no data are available concerning a possible association of PTPN22 gene with BD, and this was therefore the purpose of the study presented here. The frequencies of some alleles display great variation in different regions and ethnic groups worldwide. The International HapMap data and recent reports showed the SNP rs2476601 (1858C/T) are not polymorphic in Chinese Han populations, although they have been shown to be associated with susceptibility for immune diseases in other ethnic groups [19][21]. In Asian populations, other candidate SNPs of this gene, namely rs2488457, rs1310182 and rs3789604, were confirmed to be associated with several immune diseases, such as T1D, RA and Graves disease (GD) [22][26]. In view of these earlier findings we limited our analysis to these three SNPs (rs2488457, rs1310182 and rs3789604). The results failed to show an association of PTPN22 gene polymorphisms with risk to ocular BD.

Results and Discussion

No statistical differences were observed in the distribution of age for the Chinese Han case-control cohorts (p>0.05). There were also no significant differences in the distribution of gender for the case-control study in groups (p>0.05). The age and gender distribution of the ocular BD patients and healthy controls are shown in Table 1. The clinical features of the ocular BD patients included in our study are presented in Table 2.

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Table 1. Characteristics of the investigated ocular BD patients and healthy controls.

https://doi.org/10.1371/journal.pone.0031230.t001

A total of 516 ocular BD patients and 690 healthy controls were genotyped for three SNPs of PTPN22 (rs2488457, rs1310182 and rs3789604). The RFLP genotyping matched results obtained by direct sequencing. The genotype and allele frequencies of the three SNPs of PTPN22 examined in BD patients and healthy controls are summarized in Tables 3, 4, 5. The results showed that the distribution of genotypes and alleles did not deviate from the Hardy–Weinberg equilibrium (HWE). There were no differences concerning the genotype or allele frequencies of the three SNPs between ocular BD patients and healthy controls respectively in the two cohorts (p>0.05), and similar results were observed when comparing the combined patient cohorts with the controls (p>0.05). Under the null hypothesis (absence of association between disease and genotype/allele), OR (odd ratio) is expected to be 1.000.

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Table 3. Genotype and allele frequencies of PTPN22 polymorphisms between the ocular BD patients and healthy controls in Guangzhou.

https://doi.org/10.1371/journal.pone.0031230.t003

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Table 4. Genotype and allele frequencies of PTPN22 polymorphisms between the ocular BD patients and healthy controls in Chongqing.

https://doi.org/10.1371/journal.pone.0031230.t004

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Table 5. Genotype and allele frequencies of PTPN22 polymorphisms between the combined group of ocular BD patients and healthy controls.

https://doi.org/10.1371/journal.pone.0031230.t005

In addition, we investigated whether the PTPN22 SNPs were associated with the various clinical features of ocular BD, such as oral ulceration, genital ulceration, hypopyon, skin lesions, positive pathergy test and arthritis. The analysis did not indicate any significant association of these parameters with the tested three SNPs of PTPN22 (p>0.05) (data not shown).

Numerous factors have been reported to influence the results of the study on the association of gene polymorphisms with disease. We made the following efforts to ensure correctness of the results. The ocular BD patients were selected strictly according to the criteria of the International Study Group or the revised criteria from Behcet's Disease Research Committee of Japan if oral ulceration was not present, and two cohorts of the samples came from two independent uveitis centers in China. The healthy individual controls were recruited from the same geographical regions as the patients. No statistical differences were observed in the distribution of age and gender for the collected Chinese Han case-control cohorts. In order to validate the results of genotyping by PCR-restriction fragment length polymorphism, 10% of the samples were randomly chosen and confirmed by direct sequencing.

During recent years the PTPN22 gene has emerged as an important candidate susceptibility factor for a number of immune diseases [27]. A role of PTPN22 in clinical uveitis had been addressed in British, Turkish and Middle-East BD patients and described a limited (protective) effect of the T1858 allele in the Middle East patients but not in the UK group [17], [18]. Similarly, Martin et al showed no association between the R620W (rs2476601) of PTPN22, 1858C/T genotype and acute anterior uveitis [28]. Wagenleiter et al revealed that the above polymorphism of PTPN22 gene had no influence on Crohn's disease (CD) in Germans [29]. Matesanz et al also failed to demonstrate any correlation of the above SNP with Multiple sclerosis (MS) in Spanish patients [30]. On the other hand, an association with PTPN22 polymorphisms has consistently been reported as a susceptibility gene for a number of autoimmune diseases characterized by specific autoantibodies [20]. These studies suggest that BD, CD and MS may have a different genetic background and pathogenesis as compared with classical antibody mediated autoimmune diseases such as T1D, RA and SLE. On the other hand, autoimmunity in BD is still a controversial issue. Numerous studies suggest that BD may be mainly prone to autoinflammatory processes as opposed to autoimmunity [17], [18], [31][33]. Since PTPN22 has always been presumed to be a genetic switch for autoimmunity, the lack of an association with the common SNPs of this gene may provide additional evidence to the hypothesis that BD is autoinflammatory rather than an autoimmune disease.

Like other candidate gene research, there are some limitations in our study. The size of patient samples seems to be relatively small if the pathogenic role of the PTPN22 gene is not strong enough. The patients were only recruited from the Chinese Han population. Therefore, the association of PTPN22 polymorphisms with BD should be studied using a larger sample size and other ethnic populations. On the other hand, BD is a complex disease that affects multiple systems, and the tested patients from an ophthalmology department represent a subpopulation of this disease. The association of PTPN22 polymorphisms with BD should therefore also be investigated in BD patients from other medical departments, such as dermatology and stomatology. Finally, the present study only examined three of the PTPN22 polymorphisms, therefore it does not exclude the possibility that other SNPs of PTPN22 are associated with BD. More studies are needed to clarify these issues.

In conclusion, our study failed to find any association between the three polymorphisms of PTPN22 gene (rs2488457, rs1310182 and rs3789604) and susceptibility for ocular BD in Chinese Han patients.

Materials and Methods

Clinical Samples

Two independent Chinese Han population case-control cohorts were included in this study. Cohort 1 consisted of 251 ocular BD cases and 336 controls collected at the Zhongshan Ophthalmic Center (Guangzhou, P.R. China) from January 2005 to March 2008. Cohort 2 consisted of 265 ocular BD cases and 354 controls collected at the First Affiliated Hospital of Chongqing Medical University (Chongqing, P.R. China) from March January 2008 to May 2011. All patients had intraocular inflammation. In total, there were 516 patients with ocular BD and 690 healthy controls, whereby the comparison was performed as a case-control study in groups. Controls were not matched to case, individually or in larger groups. The proportion of male vs female is 5∶1 to 4∶1 both in the cases and controls. The diagnosis of BD was made according to the criteria of the International Study Group for BD or the revised criteria from Behcet's Disease Research Committee of Japan if oral ulceration was not present [34], [35]. The clinical characteristics of BD patients were assessed at the time of diagnosis.

Ethics statement

The protocol was approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University, Chongqing, China (Permit Number: 2009-201004), and written informed consent was obtained from all the study subjects. All procedures followed the tenets of the Declaration of Helsinki.

Genomic DNA extraction and genotyping

Blood samples were collected in EDTA tubes and kept at −70°C until used. Genomic DNA was extracted by the QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany). Amplification of the target DNA in the PTPN22 gene was analyzed by the polymerase chain reaction (PCR) using primers presented in Table 6. Each PCR reaction was performed in 10 µl containing 5 µl Premix Taq (Promega, Madison, USA), 20 pmoles primers and 0.2 µg of genomic DNA. The PCR conditions were as follow: initial denaturation at 95°C for 5 minutes followed by 37 cycles of denaturation at 94°C for 30 seconds, annealing at different temperatures (58°C for rs2488457, 58°C for rs1310182, and 60°C for rs3789604) for 30 seconds, extension at 72°C for 30 seconds, and a final extension at 72°C for 5 minutes. These SNPs were genotyped by PCR-restriction fragment length polymorphism (RFLP) analysis. PCR products of rs2488457, rs1310182 and rs3789604 polymorphisms were respectively digested with 4 U of MnlI (MBI Fermentas, Vilnius, Lithuania), Hsp92II (Promega, Madison, USA), and BseXI (MBI Fermentas, Vilnius, Lithuania) restriction enzymes (Table 6) in a 10 µl reaction volume overnight. Digestion products were visualized on a 3.5% agarose gel and stained with GoldView (SBS Genetech, Beijing, China). Randomly selected subjects (10% of all samples) were directly sequenced (Invitrogen Biotechnology, Shanghai, China) to validate the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) results.

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Table 6. Primers and restriction enzymes used for RFLP analysis of PTPN22.

https://doi.org/10.1371/journal.pone.0031230.t006

Statistical methods

Hardy-Weinberg equilibrium was tested using the χ2 test. The variable age, described as mean ± standard deviation (SD), median and range, between cases and controls was compared using the student's t-test. The variable gender was compared with Chi-square tests between cases and controls. Genotype frequencies were estimated by direct counting. Allele and genotype frequencies were compared between patients and controls by the unconditional logistic regression analysis (SAS, 9.13), which was used to compute the odds ratios (ORs) and their 95% confidence intervals (CIs). This statistical method was also performed to analyze the association between the SNPs and various clinical features of ocular BD. All statistical tests were two-sided. P<0.05 was considered significant.

Acknowledgments

We would like to thank all donors enrolled in the present study. We would like to thank Prof. Dr. Yanrong Zhou and MD. Yuanyuan Jia (Department of Health Statistics, Public Health Department of Chongqing Medical University) for advice on the statistical matters.

Author Contributions

Conceived and designed the experiments: QZ PY. Performed the experiments: QZ SH ZJ LD. Analyzed the data: QZ SH ZJ LD. Contributed reagents/materials/analysis tools: QZ SH ZJ LD FL XX. Wrote the paper: QZ AK PY.

References

  1. 1. Sakane T, Takeno M, Suzuki N, Inaba G (1999) Behcet's disease. The New England journal of medicine 341: 1284–1291.T. SakaneM. TakenoN. SuzukiG. Inaba1999Behcet's disease.The New England journal of medicine34112841291
  2. 2. Piga M, Mathieu A (2011) Genetic susceptibility to Behcet's disease: role of genes belonging to the MHC region. Rheumatology 50: 299–310.M. PigaA. Mathieu2011Genetic susceptibility to Behcet's disease: role of genes belonging to the MHC region.Rheumatology50299310
  3. 3. Karasneh J, Gul A, Ollier WE, Silman AJ, Worthington J (2005) Whole-genome screening for susceptibility genes in multicase families with Behcet's disease. Arthritis and rheumatism 52: 1836–1842.J. KarasnehA. GulWE OllierAJ SilmanJ. Worthington2005Whole-genome screening for susceptibility genes in multicase families with Behcet's disease.Arthritis and rheumatism5218361842
  4. 4. Keino H, Okada AA (2007) Behcet's disease: global epidemiology of an Old Silk Road disease. The British journal of ophthalmology 91: 1573–1574.H. KeinoAA Okada2007Behcet's disease: global epidemiology of an Old Silk Road disease.The British journal of ophthalmology9115731574
  5. 5. Verity DH, Marr JE, Ohno S, Wallace GR, Stanford MR (1999) Behcet's disease, the Silk Road and HLA-B51: historical and geographical perspectives. Tissue Antigens 54: 213–220.DH VerityJE MarrS. OhnoGR WallaceMR Stanford1999Behcet's disease, the Silk Road and HLA-B51: historical and geographical perspectives.Tissue Antigens54213220
  6. 6. Remmers EF, Cosan F, Kirino Y, Ombrello MJ, Abaci N, et al. (2010) Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease. Nature genetics 42: 698–702.EF RemmersF. CosanY. KirinoMJ OmbrelloN. Abaci2010Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease.Nature genetics42698702
  7. 7. Jiang Z, Yang P, Hou S, Du L, Xie L, et al. (2010) IL-23R gene confers susceptibility to Behcet's disease in a Chinese Han population. Annals of the rheumatic diseases 69: 1325–1328.Z. JiangP. YangS. HouL. DuL. Xie2010IL-23R gene confers susceptibility to Behcet's disease in a Chinese Han population.Annals of the rheumatic diseases6913251328
  8. 8. Mizuki N, Meguro A, Ota M, Ohno S, Shiota T, et al. (2010) Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behcet's disease susceptibility loci. Nature genetics 42: 703–706.N. MizukiA. MeguroM. OtaS. OhnoT. Shiota2010Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behcet's disease susceptibility loci.Nature genetics42703706
  9. 9. Hou S, Yang P, Du L, Zhou H, Lin X, et al. (2008) SUMO4 gene polymorphisms in Chinese Han patients with Behcet's disease. Clinical immunology 129: 170–175.S. HouP. YangL. DuH. ZhouX. Lin2008SUMO4 gene polymorphisms in Chinese Han patients with Behcet's disease.Clinical immunology129170175
  10. 10. Behrens TW (2011) Lyp breakdown and autoimmunity. Nature genetics 43: 821–822.TW Behrens2011Lyp breakdown and autoimmunity.Nature genetics43821822
  11. 11. Siminovitch KA (2004) PTPN22 and autoimmune disease. Nature genetics 36: 1248–1249.KA Siminovitch2004PTPN22 and autoimmune disease.Nature genetics3612481249
  12. 12. Gregersen PK (2005) Gaining insight into PTPN22 and autoimmunity. Nature genetics 37: 1300–1302.PK Gregersen2005Gaining insight into PTPN22 and autoimmunity.Nature genetics3713001302
  13. 13. Zhang J, Zahir N, Jiang Q, Miliotis H, Heyraud S, et al. (2011) The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness. Nature genetics 43: 902–907.J. ZhangN. ZahirQ. JiangH. MiliotisS. Heyraud2011The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness.Nature genetics43902907
  14. 14. Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, et al. (2004) A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nature genetics 36: 337–338.N. BottiniL. MusumeciA. AlonsoS. RahmouniK. Nika2004A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.Nature genetics36337338
  15. 15. Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, et al. (2004) A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. American journal of human genetics 75: 330–337.AB BegovichVE CarltonLA HonigbergSJ SchrodiAP Chokkalingam2004A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis.American journal of human genetics75330337
  16. 16. Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, et al. (2004) Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. American journal of human genetics 75: 504–507.C. KyogokuCD LangefeldWA OrtmannA. LeeS. Selby2004Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE.American journal of human genetics75504507
  17. 17. Sahin N, Bicakcigil M, Atagunduz P, Direskeneli H, Saruhan-Direskeneli G (2007) PTPN22 gene polymorphism in Behcet's disease. Tissue Antigens 70: 432–434.N. SahinM. BicakcigilP. AtagunduzH. DireskeneliG. Saruhan-Direskeneli2007PTPN22 gene polymorphism in Behcet's disease.Tissue Antigens70432434
  18. 18. Baranathan V, Stanford MR, Vaughan RW, Kondeatis E, Graham E, et al. (2007) The association of the PTPN22 620W polymorphism with Behcet's disease. Annals of the rheumatic diseases 66: 1531–1533.V. BaranathanMR StanfordRW VaughanE. KondeatisE. Graham2007The association of the PTPN22 620W polymorphism with Behcet's disease.Annals of the rheumatic diseases6615311533
  19. 19. Mori M, Yamada R, Kobayashi K, Kawaida R, Yamamoto K (2005) Ethnic differences in allele frequency of autoimmune-disease-associated SNPs. Journal of human genetics 50: 264–266.M. MoriR. YamadaK. KobayashiR. KawaidaK. Yamamoto2005Ethnic differences in allele frequency of autoimmune-disease-associated SNPs.Journal of human genetics50264266
  20. 20. Lee YH, Rho YH, Choi SJ, Ji JD, Song GG, et al. (2007) The PTPN22 C1858T functional polymorphism and autoimmune diseases–a meta-analysis. Rheumatology 46: 49–56.YH LeeYH RhoSJ ChoiJD JiGG Song2007The PTPN22 C1858T functional polymorphism and autoimmune diseases–a meta-analysis.Rheumatology464956
  21. 21. Zhang ZH, Chen F, Zhang XL, Jin Y, Bai J, et al. (2008) PTPN22 allele polymorphisms in 15 Chinese populations. International journal of immunogenetics 35: 433–437.ZH ZhangF. ChenXL ZhangY. JinJ. Bai2008PTPN22 allele polymorphisms in 15 Chinese populations.International journal of immunogenetics35433437
  22. 22. Kawasaki E, Awata T, Ikegami H, Kobayashi T, Maruyama T, et al. (2006) Systematic search for single nucleotide polymorphisms in a lymphoid tyrosine phosphatase gene (PTPN22): association between a promoter polymorphism and type 1 diabetes in Asian populations. American journal of medical genetics Part A 140: 586–593.E. KawasakiT. AwataH. IkegamiT. KobayashiT. Maruyama2006Systematic search for single nucleotide polymorphisms in a lymphoid tyrosine phosphatase gene (PTPN22): association between a promoter polymorphism and type 1 diabetes in Asian populations.American journal of medical genetics Part A140586593
  23. 23. Ichimura M, Kaku H, Fukutani T, Koga H, Mukai T, et al. (2008) Associations of protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene polymorphisms with susceptibility to Graves' disease in a Japanese population. Thyroid : official journal of the American Thyroid Association 18: 625–630.M. IchimuraH. KakuT. FukutaniH. KogaT. Mukai2008Associations of protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene polymorphisms with susceptibility to Graves' disease in a Japanese population.Thyroid : official journal of the American Thyroid Association18625630
  24. 24. Taniyama M, Maruyama T, Tozaki T, Nakano Y, Ban Y (2010) Association of PTPN22 haplotypes with type 1 diabetes in the Japanese population. Human immunology 71: 795–798.M. TaniyamaT. MaruyamaT. TozakiY. NakanoY. Ban2010Association of PTPN22 haplotypes with type 1 diabetes in the Japanese population.Human immunology71795798
  25. 25. Feng X, Li YZ, Zhang Y, Bao SM, Tong DW, et al. (2010) Association of the PTPN22 gene (−1123G>C) polymorphism with rheumatoid arthritis in Chinese patients. Tissue Antigens 76: 297–300.X. FengYZ LiY. ZhangSM BaoDW Tong2010Association of the PTPN22 gene (−1123G>C) polymorphism with rheumatoid arthritis in Chinese patients.Tissue Antigens76297300
  26. 26. Huang JJ, Qiu YR, Li HX, Sun DH, Yang J, et al. (2010) A PTPN22 promoter polymorphism −1123G>C is associated with RA pathogenesis in Chinese. Rheumatology international. JJ HuangYR QiuHX LiDH SunJ. Yang2010A PTPN22 promoter polymorphism −1123G>C is associated with RA pathogenesis in Chinese.Rheumatology international
  27. 27. Burn GL, Svensson L, Sanchez-Blanco C, Saini M, Cope AP (2011) Why is PTPN22 a good candidate susceptibility gene for autoimmune disease? FEBS letters 585: 3689–3698.GL BurnL. SvenssonC. Sanchez-BlancoM. SainiAP Cope2011Why is PTPN22 a good candidate susceptibility gene for autoimmune disease?FEBS letters58536893698
  28. 28. Martin TM, Bye L, Modi N, Stanford MR, Vaughan R, et al. (2009) Genotype analysis of polymorphisms in autoimmune susceptibility genes, CTLA-4 and PTPN22, in an acute anterior uveitis cohort. Molecular vision 15: 208–212.TM MartinL. ByeN. ModiMR StanfordR. Vaughan2009Genotype analysis of polymorphisms in autoimmune susceptibility genes, CTLA-4 and PTPN22, in an acute anterior uveitis cohort.Molecular vision15208212
  29. 29. Wagenleiter SE, Klein W, Griga T, Schmiegel W, Epplen JT, et al. (2005) A case-control study of tyrosine phosphatase (PTPN22) confirms the lack of association with Crohn's disease. International journal of immunogenetics 32: 323–324.SE WagenleiterW. KleinT. GrigaW. SchmiegelJT Epplen2005A case-control study of tyrosine phosphatase (PTPN22) confirms the lack of association with Crohn's disease.International journal of immunogenetics32323324
  30. 30. Matesanz F, Rueda B, Orozco G, Fernandez O, Leyva L, et al. (2005) Protein tyrosine phosphatase gene (PTPN22) polymorphism in multiple sclerosis. Journal of neurology 252: 994–995.F. MatesanzB. RuedaG. OrozcoO. FernandezL. Leyva2005Protein tyrosine phosphatase gene (PTPN22) polymorphism in multiple sclerosis.Journal of neurology252994995
  31. 31. Gul A (2005) Behcet's disease as an autoinflammatory disorder. Current drug targets Inflammation and allergy 4: 81–83.A. Gul2005Behcet's disease as an autoinflammatory disorder.Current drug targets Inflammation and allergy48183
  32. 32. Direskeneli H (2006) Autoimmunity vs autoinflammation in Behcet's disease: do we oversimplify a complex disorder? Rheumatology 45: 1461–1465.H. Direskeneli2006Autoimmunity vs autoinflammation in Behcet's disease: do we oversimplify a complex disorder?Rheumatology4514611465
  33. 33. Du L, Yang P, Hou S, Zhou H, Kijlstra A (2009) No association of CTLA-4 polymorphisms with susceptibility to Behcet disease. The British journal of ophthalmology 93: 1378–1381.L. DuP. YangS. HouH. ZhouA. Kijlstra2009No association of CTLA-4 polymorphisms with susceptibility to Behcet disease.The British journal of ophthalmology9313781381
  34. 34. (1990) Criteria for diagnosis of Behcet's disease. International Study Group for Behcet's Disease. Lancet 335: 1078–1080.1990Criteria for diagnosis of Behcet's disease. International Study Group for Behcet's Disease.Lancet33510781080
  35. 35. Japan BsDRCo (2003) The revised criteria and manual of treatments of Behcet's disease. Tokyo: Ministry of Health and Welfare. pp. 11–29.Japan BsDRCo2003The revised criteria and manual of treatments of Behcet's diseaseTokyoMinistry of Health and Welfare1129