|Year : 2017 | Volume
| Issue : 4 | Page : 214-218
The protein tyrosine phosphatase, nonreceptor type 22-1858C->T (rs2476601) polymorphism is not a genetic risk factor for systemic lupus erythematosus in Indian Tamils
Panneer Devaraju1, Reena Gulati2, Durga Prasanna Misra3, Vir Singh Negi1
1 Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
2 Department of Pediatrics, Genetic Services Unit, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
3 Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
|Date of Web Publication||16-Nov-2017|
Vir Singh Negi
Department of Clinical Immunology, SSB 4th Floor, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanwantari Nagar, Puducherry - 605 006
Source of Support: None, Conflict of Interest: None
Background: Systemic lupus erythematosus (SLE), a systemic autoimmune disease, occurs due to disruption of immune homeostasis against self-antigens. The etiology of SLE is complex and multiple genetic factors contribute to disease susceptibility and clinical phenotypes. Protein tyrosine phosphatase, nonreceptor type 22 (PTPN22) is a lymphoid-specific phosphatase that negatively regulates T-cell receptor signaling and is responsible for the maintenance of T-cell homeostasis. Genetic aberrations affecting the function of PTPN22 result in the proliferation of autoreactive T-cells and development of autoimmune diseases.
Methods: We carried out a case–control genetic study to analyze the association of PTPN22 R620W polymorphism (rs2476601) with disease susceptibility and clinical and autoantibody profile in Indian Tamils with SLE. Three hundred SLE patients satisfying the 1997 revised American College of Rheumatology classification criteria for SLE were enrolled in the study. Disease activity was measured using the SLE Disease Activity Index. We recruited 460 age-, sex-, and ethnicity-matched individuals without a family history of autoimmune diseases as control population. Genomic DNA was extracted from the blood sample by salting-out method. The PTPN22-1858C->T (rs2476601) polymorphism was screened by polymerase chain reaction-restriction fragment length polymorphism.
Results: The frequency of the ancestral allele “C” was similar in both cases and controls (99.3% and 99.8%, respectively) and the mutant allele “T” was less frequent in South Indian Tamil population; it did not influence clinical or serological phenotypes.
Conclusion: Our findings suggest that the PTPN22 (rs2476601) polymorphism is less frequent and did not confer a risk for lupus or its associated clinical or serological phenotypes in South Indian Tamils.
Keywords: Autoantibodies, polymorphism, protein tyrosine phosphatase, nonreceptor type 22, susceptibility, systemic lupus erythematosus
|How to cite this article:|
Devaraju P, Gulati R, Misra DP, Negi VS. The protein tyrosine phosphatase, nonreceptor type 22-1858C->T (rs2476601) polymorphism is not a genetic risk factor for systemic lupus erythematosus in Indian Tamils. Indian J Rheumatol 2017;12:214-8
|How to cite this URL:|
Devaraju P, Gulati R, Misra DP, Negi VS. The protein tyrosine phosphatase, nonreceptor type 22-1858C->T (rs2476601) polymorphism is not a genetic risk factor for systemic lupus erythematosus in Indian Tamils. Indian J Rheumatol [serial online] 2017 [cited 2022 Jul 4];12:214-8. Available from: https://www.indianjrheumatol.com/text.asp?2017/12/4/214/218551
| Introduction|| |
Systemic lupus erythematosus (SLE) is the archetypal autoimmune disease with a complex etiology. The higher incidence of this disease within family members suggests an underlying genetic predisposition toward this disease. In common with other autoimmune diseases, development of self-reactive T- and B-cells is a common feature in lupus, suggesting a disruption in immune homeostasis. Cytotoxic T-lymphocyte-associated protein 4 and protein tyrosine phosphatase, nonreceptor type 22 (PTPN22) are the major immune molecules associated with T-cell homeostasis. Therefore, any genetic or extraneous factors affecting their function can augment the rise of autoreactive T-cells in circulation and lead to the development of autoimmune diseases.,PTPN22 is a lymphoid-specific phosphatase which inhibits T-cell proliferation. PTPN22 gene knockout mice exhibited features of splenomegaly, lymphadenopathy, increased proliferation of lymphocytes, and cytokine production. Their lymph nodes had spontaneous development of germinal centers, T- and B-lymphocytosis coupled with increased IgG secretion. In humans, the +1858 C to T (rs2476601)/R620W/LypW polymorphism in exon 14 of PTPN22 gene was reported to disrupt the negative regulation of T-cells, hence favoring the autoreactive T-cells to escape from the process of negative selection in the thymus and reach the peripheral circulation to intensify autoimmune responses. Furthermore, this polymorphism has a negative impact on regulatory T-cells, thereby affecting peripheral tolerance against self-antigens. The PTPN22 R620W polymorphism in human was reported be a risk factor for type 1 diabetes mellitus (T1D), rheumatoid arthritis (RA), SLE, and Grave's disease. In addition, it was reported to augment susceptibility to infectious diseases., Lupus in Indians is associated with poorer disease outcome compared to the West, and its genetics in this population, especially South Indian Tamils, is yet to be fully explored. Hence, this genetic study was carried out to study the influence of PTPN22 R620W polymorphism on the development of SLE and its clinical features in the Indian Tamil population.
| Methods|| |
The study group comprised 300 patients with SLE attending the Clinical Immunology outpatient services at Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry. All patients fulfilled the 1997 American College of Rheumatology criteria for SLE  and their disease activity was assessed and graded using the SLE Disease Activity Index (SLEDAI). Qualitative analysis of antinuclear autoantibodies was done using anti-nuclear antibody immunoblot kit (Euroimmun lab diagnostics, Germany). Anti-double-stranded deoxyribonucleic acid antibody, antiphospholipid antibodies, i.e., IgM and IgG anti-cardiolipin antibody, and IgM and IgG anti-β2 glycoprotein I antibody were measured using commercial ELISA kits (Aeskulisa®, Germany). Complement components C3 and C4 were measured by nephelometry (Dade Behring, Germany). Genomic DNA was extracted from 5 ml venous blood by salting-out procedure. The PTPN22-1858C->T (rs2476601) polymorphism was screened by polymerase chain reaction-restriction fragment length polymorphism following the steps described in a previously published protocol.
This study was approved by the institute's Ethics Committee. A signed informed consent was obtained from all the participants.
| Results|| |
Serological and clinical features of systemic lupus erythematosus in case group
The group of cases included in our study had 300 patients with SLE (279 females and 21 males), whereas the control group comprised 460 individuals (420 females and 40 males) with similar age, sex, and ethnic background. The mean age of the cases and controls was 29.9 ± 9.6 and 33 ± 12 years, respectively. In our patients with lupus, the observed average age of disease onset was 25.5 ± 8.4 years and the disease duration was 72.5 ± 40 months. The mean SLEDAI score was 14.6 ± 7.9, suggesting that all the patients had active disease at the time of study. The clinical manifestations observed were mucocutaneous involvement (82.3%), inflammatory arthritis (70%), hematological involvement (49%) (leucopenia [37.3%]/anemia [20%]/thrombocytopenia [23%]), lupus nephritis (44%), neuro-psychiatric lupus (28%), vasculitis (28%), serositis (17%), and secondary antiphospholipid antibody syndrome (12%). The autoantibody profile and the mean complement level of C3 and C4 of the patients are summarized in [Table 1]. The complement components C3 and C4 were observed to be low in 40% and 34% of patients, respectively.
|Table 1: Serological phenotype and complement component C3 and C4 status in systemic lupus erythematosus|
Click here to view
Genotype distribution of protein tyrosine phosphatase, nonreceptor type 22-1858C->T (rs2476601) polymorphism and its influence on disease susceptibility and clinical features
Genotype analysis of PTPN22 1858C->T (rs2476601) polymorphism in both the patients and controls revealed that mutant allele T was a rare variant in the South Indian Tamil population. The R620W polymorphism was less frequent in our study and the observed ancestral allele frequencies in controls and cases were 99.3% and 99.8%, respectively. Our findings suggest that the mutant PTPN22 is less frequent in South Indian Tamils [Table 2]. Hence, this polymorphism failed to confer significant genetic risk to develop SLE. In addition, it also failed to confer significant influence over specific clinical or serological phenotypes in our patients with lupus.
|Table 2: Frequency of protein tyrosine phosphatase, nonreceptor type 22 1858 C - >T (rs2476601) polymorphism in Indian Tamils|
Click here to view
| Discussion|| |
Prior genetic studies in humans and gene knockout studies in animal models suggest that the polymorphic PTPN22 gene is a potent genetic risk factor that could trigger autoimmunity. A meta-analysis revealed that the PTPN22 T allele has a strong association with numerous autoimmune diseases including generalized vitiligo, immune thrombocytopenia, T1D, RA, Graves' disease, juvenile idiopathic arthritis, myasthenia gravis, antineutrophil cytoplasmic antibody-associated vasculitis, and Addison's disease. A large number of case–control studies in different ethnic populations also revealed that the PTPN22 R620W polymorphism was one among the key genetic risk factors predisposing toward the development of SLE in Caucasians.,
To the best of our knowledge, this is the first genetic study conducted in an Indian population, more so in a South Indian Tamil population, to test the influence of PTPN22 R620W polymorphism with the development of SLE. In Caucasians, the reported mutant allele frequency ranged between 2.1% and 15.5%. However, in Asian and African populations, the mutant allele frequency ranged between 0% and 2%., In our study, the PTPN22 R620W polymorphism was less frequent (<1%). Our findings are in concordance with the earlier reports in Asian and African populations., Hence, we observed that the less frequent PTPN22 620W polymorphism failed to confer significant risk for SLE in Indian Tamils. A study conducted in western region of India to test the influence of PTPN22 R620W with the development of RA exposed that this polymorphism was less frequent and failed to confer susceptibility to develop RA. In contrast to the above findings, a study in a North Indian population revealed that the PTPN22 620W polymorphism was an independent risk factor to develop T1D, even in the presence of other major risk factors such as human leukocyte antigen alleles such as DRB1*03:01, DRB1*04:01, and DRB1*04:05. Differences observed in disease susceptibility can be attributed to the genetic heterogeneity across different ethnicities and the prevailing environmental conditions. In addition to the above, other potential variants within the coding and noncoding regions of the gene and complex genetic interactions may also influence disease susceptibility.
In addition to the PTPN22 R620W polymorphism, other variants within the PTPN22 gene were reported to affect the PTPN22 activity and predispose to autoimmune diseases. The PTPN22 788G>A (rs33996649) variant was reported to confer protection against the development of RA in Caucasians, regardless of the presence of PTPN22 R620W polymorphism. Orrú et al. reported that the Q263 variant affects the phosphatase activity of PTPN22 and thus conferred protection against the development of SLE in Caucasians. Kawasaki et al. first reported that PTPN22-1123GtoC polymorphism predisposed Japanese and Koreans to acute onset of T1D. Viken et al. observed that the PTPN22-1123C was in linkage disequilibrium with PTPN22 R620W polymorphism and was a risk allele for RA in Norwegians. Huang et al., 2010, and Feng et al., 2010, reported that the PTPN22-1123G to C was a risk factor for RA in Chinese population., Another intronic variant of PTPN22 rs1217414 C/T has been implicated in early-onset psoriasis in a British population  and SLE in European-Americans, but was found to exert a protective effect against ankylosing spondylitis in Chinese population. A limitation of our study was that we could screen only the PTPN22 R620W polymorphism; despite its absence, the incidence of SLE in our population is high and with poor disease outcome. Hence, the influence of the other variants in PTPN22 gene if studied would help us to identify the population-specific risk variants in the gene and its role in the disease pathogenesis.
The less frequent PTPN22 R620W polymorphism in our study group also failed to influence the clinical or serological features of the disease. However, PTPN22 620W allele was reported to favor the production of anti-cyclic citrullinated peptide antibodies and rheumatoid factor in RA patients, which was replicated in many studies across different ethnic populations.,,, An association of PTPN22 620W allele with childhood onset of SLE in Mexican population  and juvenile idiopathic arthritis in Greeks  was reported but lacked replication in other populations.
Our present study shows that unlike other Asian and African ethnic populations, the PTPN22 R620W polymorphism is not frequent in Indian Tamils. It does not influence the susceptibility and clinical features of SLE. A comprehensive analysis of other potential variants of the PTPN22 gene may help to identify the risk alleles and their role in SLE pathogenesis in our population.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Vyse TJ, Kotzin BL. Genetic susceptibility to systemic lupus erythematosus. Annu Rev Immunol 1998;16:261-92.
Gregersen PK, Lee HS, Batliwalla F, Begovich AB. PTPN22: Setting thresholds for autoimmunity. Semin Immunol 2006;18:214-23.
Bottini N, Peterson EJ. Tyrosine phosphatase PTPN22: Multifunctional regulator of immune signaling, development, and disease. Annu Rev Immunol 2014;32:83-119.
Vang T, Congia M, Macis MD, Musumeci L, Orrú V, Zavattari P, et al.
Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet 2005;37:1317-9.
Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, et al.
A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 2004;36:337-8.
Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, et al.
A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 2004;75:330-7.
Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, Carlton VE, et al.
Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet 2004;75:504-7.
Heward JM, Brand OJ, Barrett JC, Carr-Smith JD, Franklyn JA, Gough SC, et al.
Association of PTPN22 haplotypes with graves' disease. J Clin Endocrinol Metab 2007;92:685-90.
Gomez LM, Anaya JM, Martin J. Genetic influence of PTPN22 R620W polymorphism in tuberculosis. Hum Immunol 2005;66:1242-7.
Lamsyah H, Rueda B, Baassi L, Elaouad R, Bottini N, Sadki K, et al.
Association of PTPN22 gene functional variants with development of pulmonary tuberculosis in Moroccan population. Tissue Antigens 2009;74:228-32.
Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725.
Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI. A disease activity index for lupus patients. The committee on prognosis studies in SLE. Arthritis Rheum 1992;35:630-40.
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215.
Baca V, Velázquez-Cruz R, Salas-Martínez G, Espinosa-Rosales F, Saldaña-Alvarez Y, Orozco L, et al.
Association analysis of the PTPN22 gene in childhood-onset systemic lupus erythematosus in Mexican population. Genes Immun 2006;7:693-5.
Bottini N, Vang T, Cucca F, Mustelin T. Role of PTPN22 in type 1 diabetes and other autoimmune diseases. Semin Immunol 2006;18:207-13.
Zheng J, Ibrahim S, Petersen F, Yu X. Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue. Genes Immun 2012;13:641-52.
Orozco G, Sánchez E, González-Gay MA, López-Nevot MA, Torres B, Cáliz R, et al.
Association of a functional single-nucleotide polymorphism of PTPN22, encoding lymphoid protein phosphatase, with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Rheum 2005;52:219-24.
Eliopoulos E, Zervou MI, Andreou A, Dimopoulou K, Cosmidis N, Voloudakis G, et al.
Association of the PTPN22 R620W polymorphism with increased risk for SLE in the genetically homogeneous population of Crete. Lupus 2011;20:501-6.
Mori M, Yamada R, Kobayashi K, Kawaida R, Yamamoto K. Ethnic differences in allele frequency of autoimmune-disease-associated SNPs. J Hum Genet 2005;50:264-6.
Chabchoub G, Teixiera EP, Maalej A, Ben Hamad M, Bahloul Z, Cornelis F, et al
. The R620W polymorphism of the protein tyrosine phosphatase 22 gene in autoimmune thyroid diseases and rheumatoid arthritis in the Tunisian population. Ann Hum Biol 2009;36:342-9.
Pradhan VD, Dalvi H, Parsannavar D, Rajadhyaksha A, Patwardhan M, Ghosh K. Study of PTPN22 1858C/T polymorphism in rheumatoid arthritis patients from Western India. India J Rheumatol 2012;7:130-4.
Rani R, Israni N, Kumar A, Vasudevan S, Singh J. Association of protein tyrosine phosphatase non-receptor, Type 22 (PTPN22) C1858T Polymorphism with Type 1 diabetes in North India: A replication study. J Diab Metab 2014;5:342.
Rodríguez-Rodríguez L, Taib WR, Topless R, Steer S, González-Escribano MF, Balsa A, et al.
The PTPN22 R263Q polymorphism is a risk factor for rheumatoid arthritis in Caucasian case-control samples. Arthritis Rheum 2011;63:365-72.
Orrú V, Tsai SJ, Rueda B, Fiorillo E, Stanford SM, Dasgupta J, et al.
A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus. Hum Mol Genet 2009;18:569-79.
Kawasaki E, Awata T, Ikegami H, Kobayashi T, Maruyama T, Nakanishi K, et al.
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. Am J Med Genet A 2006;140:586-93.
Viken MK, Olsson M, Flåm ST, Førre O, Kvien TK, Thorsby E, et al.
The PTPN22 promoter polymorphism -1123G> C association cannot be distinguished from the 1858C & gt; T association in a Norwegian rheumatoid arthritis material. Tissue Antigens 2007;70:190-7.
Huang JJ, Qiu YR, Li HX, Sun DH, Yang J, Yang CL, et al.
A PTPN22 promoter polymorphism -1123G> C is associated with RA pathogenesis in Chinese. Rheumatol Int 2012;32:767-71.
Feng X, Li YZ, Zhang Y, Bao SM, Tong DW, Zhang SL, et al.
Association of the PTPN22 gene (-1123G> C) polymorphism with rheumatoid arthritis in Chinese patients. Tissue Antigens 2010;76:297-300.
Smith RL, Warren RB, Eyre S, Ke X, Young HS, Allen M, et al.
Polymorphisms in the PTPN22 region are associated with psoriasis of early onset. Br J Dermatol 2008;158:962-8.
Namjou B, Kim-Howard X, Sun C, Adler A, Chung SA, Kaufman KM, et al.
PTPN22 association in systemic lupus erythematosus (SLE) with respect to individual ancestry and clinical sub-phenotypes. PLoS One 2013;8:e69404.
Tang L, Wang Y, Chen BF. A variant within intron 1 of the PTPN22 gene decreases the genetic susceptibility of ankylosing spondylitis in a central south Chinese Han population. Scand J Rheumatol 2014;43:380-4.
Karlson EW, Chibnik LB, Cui J, Plenge RM, Glass RJ, Maher NE, et al.
Associations between human leukocyte antigen, PTPN22, CTLA4 genotypes and rheumatoid arthritis phenotypes of autoantibody status, age at diagnosis and erosions in a large cohort study. Ann Rheum Dis 2008;67:358-63.
Stanford SM, Bottini N. PTPN22: The archetypal non-HLA autoimmunity gene. Nat Rev Rheumatol 2014;10:602-11.
Goulielmos GN, Chiaroni-Clarke RC, Dimopoulou DG, Zervou MI, Trachana M, Pratsidou-Gertsi P, et al.
Association of juvenile idiopathic arthritis with PTPN22 rs2476601 is specific to females in a Greek population. Pediatr Rheumatol Online J 2016;14:25.
[Table 1], [Table 2]