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 Table of Contents  
Year : 2017  |  Volume : 12  |  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

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 Publication16-Nov-2017

Correspondence Address:
Vir Singh Negi
Department of Clinical Immunology, SSB 4th Floor, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanwantari Nagar, Puducherry - 605 006
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_90_17

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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 Jun 27];12:214-8. Available from:

  Introduction Top

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.[1] Cytotoxic T-lymphocyte-associated protein 4 and protein tyrosine phosphatase, nonreceptor type 22 (PTPN22) are the major immune molecules associated with T-cell homeostasis.[2] 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.[1],[2]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.[3] 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.[4] 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),[5] rheumatoid arthritis (RA),[6] SLE,[7] and Grave's disease.[8] In addition, it was reported to augment susceptibility to infectious diseases.[9],[10] 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 Top

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 [11] and their disease activity was assessed and graded using the SLE Disease Activity Index (SLEDAI).[12] 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.[13] 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.[14]

Ethical approval

This study was approved by the institute's Ethics Committee. A signed informed consent was obtained from all the participants.

  Results Top

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

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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

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  Discussion Top

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.[15] 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.[16] 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.[17],[18]

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%.[18] However, in Asian and African populations, the mutant allele frequency ranged between 0% and 2%.[19],[20] 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.[19],[20] 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.[21] 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.[22] 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.[23] 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.[24] Kawasaki et al. first reported that PTPN22-1123GtoC polymorphism predisposed Japanese and Koreans to acute onset of T1D.[25] 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.[26] 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.[27],[28] Another intronic variant of PTPN22 rs1217414 C/T has been implicated in early-onset psoriasis in a British population [29] and SLE in European-Americans,[30] but was found to exert a protective effect against ankylosing spondylitis in Chinese population.[31] 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.[6],[21],[32],[33] An association of PTPN22 620W allele with childhood onset of SLE in Mexican population [14] and juvenile idiopathic arthritis in Greeks [34] 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 Top

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  [Table 1], [Table 2]


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