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E-IJD® - ORIGINAL ARTICLE
Year : 2022  |  Volume : 67  |  Issue : 3  |  Page : 311
CTLA4 gene polymorphism and its association with disease occurrence, clinical manifestations, serum markers and cytokine levels in SLE patients from North India


1 Department of Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
2 Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Date of Web Publication22-Sep-2022

Correspondence Address:
Jyotsna Kailashiya
Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi - 221 005, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.ijd_82_22

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   Abstract 


Background: Cytotoxic T lymphocyte-associated protein-4 (CTLA-4) or CD152 is an inhibitory receptor expressed constitutively on CD4+CD25+ T regulatory lymphocytes (Treg) and transiently on activated CD4+ and CD8+ T lymphocytes. Association of CTLA4 gene polymorphisms with Systemic Lupus Erythematosus (SLE) has been reported in south Indians, but not in north Indians. This study aims to investigate CTLA4 gene polymorphism and its association with the occurrence of SLE, its clinical manifestation and serological markers in north Indians. Methods: This cross sectional study was done in a tertiary health care centre in north India. Patients reporting to the hospital and diagnosed with systemic lupus erythematosus were included in study. +49 A/G (snp- rs231775) CTLA4 gene polymorphism was analysed in 41 SLE patients and 21 matched healthy controls by real time PCR method. ANA (Antinuclear Antibody), anti dsDNA, Interferon-γ (IFN- γ), TGF-β, IL-10 were measured by ELISA kits. Complement (C3 and C4) and immunoglobulins (IgA, IgG, IgM) estimation were done with the turbidometry method. Chi-square test was used for comparison between groups and odds ratio with 95% confidence interval was calculated to estimate the associated risk. Results: A/A genotype was most common (51.2%) followed by the A/G genotype (46.3%) and G/G genotype (2.4%, detected in only 1 patient). The frequency of A allele was 74.4%, while of G allele was only 25.6%. A/G genotype SLE patients showed a higher risk (odds ratio 37.5, 95% CI- 6.048-232.51) of developing edema compared to A/A genotype patients. There was no statistically significant association of various CTLA4 genotypes with the occurrence of SLE and serum markers. Conclusions: A/A was the most common CTLA4 genotype in both SLE patients and healthy controls of north India. Contrary to the previous report in south Indians, there was no statistically significant association between CTLA4 genotype and occurrence of SLE in north Indians. Only the presence of generalised edema was found significantly associated with the A/G genotype.


Keywords: Autoimmine disease, CTLA4, cytokine, polymorphisms, systemic lupus erythematosus


How to cite this article:
Kailashiya V, Singh U, Kailashiya J. CTLA4 gene polymorphism and its association with disease occurrence, clinical manifestations, serum markers and cytokine levels in SLE patients from North India. Indian J Dermatol 2022;67:311

How to cite this URL:
Kailashiya V, Singh U, Kailashiya J. CTLA4 gene polymorphism and its association with disease occurrence, clinical manifestations, serum markers and cytokine levels in SLE patients from North India. Indian J Dermatol [serial online] 2022 [cited 2022 Sep 30];67:311. Available from: https://www.e-ijd.org/text.asp?2022/67/3/311/356763





   Introduction Top


Cytotoxic T lymphocyte-associated protein-4 (CTLA-4) or CD152 is an inhibitory receptor expressed constitutively on CD4+CD25+ T regulatory lymphocytes (Treg) and transiently on activated CD4+ and CD8+ T lymphocytes and a few non-lymphoid cells.[1],[2] CTLA-4 acts as a negative regulator of T cell responses by interacting with B7 molecules B7.1 (CD80) and B7.2 (CD86)) on antigen-presenting cells; in contrast, a co-stimulatory signal is evoked by CD28-B7 interaction.[3],[4] CTLA-4 has a greater affinity for the B7 molecule than CD28 and it downregulates T-cell function. This downregulation promotes long lived anergy in T cells and prevents autoimmunity. Its abnormal expression is believed to play role in the abnormal activation of T cells in systemic lupus erythematosus (SLE).[5]

CTLA-4 is encoded by CTLA4 gene in humans. The CTLA4 gene is located on chromosome 2q33.[4],[6] Various single nucleotide polymorphisms (SNPs) in the CTLA4 gene have been implicated in susceptibility to autoimmune disorders including Graves disease,[7],[8] type 1 diabetes mellitus,[9] celiac disease,[10],[11],[12] Addison's disease,[13] autoimmune thyroid disease,[14],[15],[16] rheumatoid arthritis[17] and SLE.[18],[19] Mutations in CTLA4 have been found to be associated with extensive infiltration of CD4 T cells in various organs.[20] The important and fine function of CTLA-4 in inducing immune modulatory and hemostatic signals in the ongoing immune response poised this molecule under evolutionary pressure to go in the process of the point mutation in CTLA4 and polymorphism within the population and along the species. There are at least three well-studied polymorphic markers that have drawn the most attention: a C-to-T substitution at position 318 (C-318T) of the promoter region,[21] an A-to-G transition at position 49 of exon 1 (A49G) which causes a threonine-to-alanine substitution in codon 17 of the leader peptide (A17T)[9] and an (AT) n dinucleotide repeat polymorphism located in the 3' non translated region of exon 4.[22] Only A49G transition polymorphism changes an amino acid from alanine to threonine in the leader sequence. It is postulated that this change may affect the processing of CTLA-4 in ER and result in less efficient glycosylation and reduced expression of membrane CTLA-4 protein.[9],[23],[24] Mutations in CTLA4 have been found to be associated with extensive infiltration of CD4 T cells in various organs. This mutation-induced abnormal expression of CTLA-4 is believed to play a role in the abnormal activation of T cells in SLE.[24]

CTLA4 gene polymorphisms have been previously investigated in SLE patients from different ethnic populations, in many countries, which show highly inconsistent findings.[24] Heward et al.,[25] 1999, reported no association between CTLA4 and SLE in Caucasian patients. Later, Lee et al., 2001, Liu et al., 2001, Aguilar et al., 2003, Chua et al., 2010, confirmed Heward's findings indicating no association between SLE and CTLA4 gene polymorphism in Korean, Chinese, Spanish and Malaysian populations.[26],[27],[28],[29] However, Ahemed et al.,[30] 2001, reported an allele G of CTLA4 polymorphism at the leader sequence to be associated with susceptibility to SLE in the Japanese population. Most of these reports investigated the SNP at position +49 of the leader sequence. One meta analysis found a significant association between the risk of SLE and the GG genotype of exon-1 at position +49 in the leader peptide. The overall odds ratio for the CTLA4 exon-1 +49 GG genotype was 1.287 (95% CI = 1.058–1.564, P = 0.011). Therefore, this report indicated results contrary to those of previous sporadic publications with inconsistent results, demonstrating a clearly strong association of the CTLA4 gene at position +49A/G with SLE, particularly in Asian and with a lesser degree in the European population.[18],[19] Another meta analysis published later again contradicted previous reports and concluded no association between the risk of SLE and CTLA polymorphism.[31]

A previous study from India itself reported that CTLA4 +49 A/G polymorphism is a potential genetic risk factor for lupus susceptibility in South Indian Tamils.[32] Apart from these epidemiological studies, there is limited data available to describe the role of CTLA4 SNPs in clinical manifestations and pathogenesis of SLE. We have conducted this study to find an association between CTLA4 gene polymorphism (+49 A/G, SNP- rs231775), the occurrence of SLE in the north Indian population and to find the associated risk of developing various clinical manifestations and abnormal serum markers in SLE patients.


   Methods Top


The +49 A/G (snp- rs231775) CTLA4 gene polymorphism was analysed in 41 SLE patients and 21 matched healthy controls who agreed to participate in this study. Patients exhibiting symptoms of SLE, reporting to Division of Rheumatology, Department of Medicine, Sir Sunderlal Hospital, Banaras Hindu University, Varanasi, Uttar Pradesh were selected after confirmed diagnosis. The diagnosis was confirmed by immunological and clinical criteria laid down by the American College of Rheumatology (ACR). Healthy controls were also taken from the same centre. This study was approved by the ethical committee of Institute of Medical Sciences, Banaras Hindu University, Varanasi and informed consent was taken from all participants.

Two ml peripheral venous blood was taken in an EDTA vial for CTLA4 gene study by PCR (polymerase chain reaction). A total of 4 ml of blood was taken in the plain vial for testing serum Immunoglobulin, Complements, ANA (antinuclear antibody), anti-dsDNA Ab (double stranded DNA antibody), IFN-γ (interferon gamma), transforming growth factor beta (TGF-β) and Interleukin-10 (IL-10) estimation. Serum was stored at -20°C and EDTA blood were stored at -80°C till analysis.

ELISA kits were used for estimation of Antinuclear Antibody (ANA) (Euro Diagnostica, Sweden), anti dsDNA (Euro Diagnostica, Sweden), Interferon-γ (IFN- γ) (AssayMax Human IFN-γ ELISA Kit), TGF-β (AssayMax Human LAP TGF-β1 ELISA Kit), IL-10 (AssayMax Human IL-10 ELISA Kit). Complement (C3 and C4) and immunoglobulins (IgA, IgG, IgM) estimation were done using SPINREACT kits, with Quantiamate Turbidometer of Tulip Diagnostics by turbidometry method. All reference levels were followed as given in the kit description. Detection of autoantibodies against Sm, RNP, SSA/Ro and SSB/La antigens was done by D-tek BlueDot ANA8D IgG Immunodot kit. All reference ranges were taken as per test kit description.

CTLA-4 gene polymorphism study (+49 A/G snp-231775)

DNA was isolated from EDTA blood and Real Time PCR of Applied Biosystems StepOne™ was used for DNA amplification. The NCBI identity number for the SNP genotyping rs231775 for +49 A/G loci was manufactured by Invitrogen Bioservices India Pvt Lt TaqMan® SNP Genotyping Assays. The procedure for the assay was strictly followed as prescribed by the manufacturer.

Statistical analysis

All statistical analyses were performed using SPSS version 20 (SPSS Inc., Chicago, IL, USA). Chi-square Pearson test was used to find difference between presence of clinical manifestations and abnormal serum markers among various genotypes. Odds ratio and 95% confidence interval were calculated to estimate the associated risk. Student t test was performed to find the difference between parametric variables (serum concentrations of various markers). A P value of less than 0.05 (P < 0.05) was considered as statistically significant.


   Results Top


Out of 41 SLE patients included in this study, 34 (82.9%) were females and 7 (17.1%) were males. Mean age of the patients was 34.15 years, with a standard deviation of 10.55 years, and ranged from 16 years to 58 years. All patients were positive for ANA. Polymorphism at exon-1 +49 A/G position produces three genotypes, A/A, A/G and G/G. In SLE patients, we found that the A/A genotype was most common (51.2%) followed by the A/G genotype (46.3%) and G/G genotype (2.4%, detected in only 1 patient). The frequency of the A allele was 74.4%, while of G allele was only 25.6%. Similarly, in healthy controls, the A/A genotype was most common (61.9%), followed by the A/G genotype (38.1%). None of the healthy control showed G/G genotype. The frequency of the A allele was 80.9% while of G allele was only 19.1% in healthy controls [Table 1].
Table 1: Comparison of CTLA4 gene polymorphism (+49 A/G, SNP-rs231775) among SLE patients and healthy controls

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Among clinical manifestations in SLE patients, only generalized edema showed a statistically significant difference between A/A and A/G genotypes in SLE patients. A/G genotype SLE patients showed a higher risk (odds ratio 37.5, 95% CI- 6.048-232.51) of developing edema than A/A genotype patients [Table 2]. The rest of the symptoms and all measured serum markers did not show any statistically significant difference among different genotypes [Table 2] and [Table 3].
Table 2: Association of disease symptoms and CTLA4 gene polymorphism (+49 A/G, SNP-rs231775) in SLE patients

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Table 3: Association of serum markers and CTLA4 gene polymorphism (+49 A/G, SNP-rs231775) in SLE patients

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   Discussion Top


A/A genotype was most common in both SLE patients and healthy controls. Although the frequency of A/G genotype was higher (46.3%) in SLE patients as compared to healthy controls (38.1%) with odds ratio of 1.40 (95% CI- 0.47- 4.10), there was no statistically significant association between the presence of CTLA4 polymorphisms and occurrence of SLE [Table 1]. Different past studies on CTLA4 polymorphism for susceptibility of development of SLE have given variable results. Although most of the studies show no significant association of SLE with CTLA4+49 A/G polymorphism,[23],[26],[27],[28],[33],[34],[35] few studies have shown an association of A/G phenotype with increased risk of SLE.[30],[32] Devraju et al.[32] (2014) and Katkam et al.[36] (2015) conducted their study on the South Indian population and found a significant association between the risk of SLE and A/G, G/G genotype and G allele. In contrast to these reports, we did not find any statistically significant association between the risk of SLE and CTLA4+49 A/G polymorphism in North Indians.

Additionally, we also examined the risk of the presence of various clinical manifestations and serum markers in SLE patients associated with different CTLA4 genotypes [Table 2] and [Table 3]. It was observed that SLE patients having the A/G genotype showed a much higher risk of developing generalized edema compared to the A/A genotype [Table 2]. Total of 17 patients (41.46%) presented with generalized edema, out of which 15 had A/G genotype (79.9% of total A/G genotype) and only two had A/A genotype (9.5% of total A/A genotype). The presence of generalised edema is suggestive of renal damage and lupus nephritis,[37],[38] although the present study does not provide conclusive evidence of renal involvement in SLE patients' A/G genotype. Genetic predisposition of renal involvement in SLE has already been reported for APOL1 (Apolipoprotein L1) variants.[39] Contrary to our finding, an earlier study in the Iranian population reported no association between CTLA4 genotypes and the presence of renal involvement.[40] About 10% of lupus nephritis patients end up developing end stage renal disease and chronic kidney disease, making it a major risk factor for mortality and morbidity in SLE. A preventive management strategy in SLE patients with A/G genotype can be applied to reduce renal complications.[41] In clinical settings, if SLE patients can afford this test, genotyping may be used to predict generalised edema. Close monitoring and follow up of patients having A/G genotype can be done for the prediction of generalized edema and possible lupus nephritis. Although further large-scale research, including renal biopsy, is required to confirm renal involvement in the A/G genotype.

In a similar previous study in the Iranian population,[40] the clinical manifestations (other than generalised edema) did not show any significant difference between different genotypes, similar to our findings. The presence of anti-SSA Ab, anti-SSB Ab, and low IgG was relatively more common in the A/G genotype, Anti Sm Ab, Anti RNP Ab, low IgM and high IgA were more common in A/A genotypes [Table 3].

The presence of Anti dsDNA antibodies, C3 and C4 levels are also used as conventional serum biomarkers in SLE. Anti dsDNA antibody deposition and complement activation play a major role in the pathogenesis of renal complications in SLE.[42] Showing complement level deficiency, a total of 87.8% of the patient showed low C3 and 43.9% showed low C4 serum levels. A total of 16 (39%) out of 41 patients showed the presence of serum anti-dsDNA antibodies. 52% of total A/G and only 3.5% of total A/A genotype patients were positive for dsDNA antibodies. A/G genotype showed a relatively higher presence of dsDNA antibodies compared to the A/A genotype [Table 3], supporting the observation of a higher risk of generalised edema and possible renal involvement in the A/G genotype.

An imbalance between inflammatory and anti-inflammatory cytokines has already been noticed in SLE pathogenesis.[43] Anti-dsDNA antibodies and immune complexes are known to trigger IL-10 production by monocytes and B cells.[44],[45] Serum IL 10 titres have been found to be higher in SLE patients and positively correlated with disease activity and anti-DNA antibody titers, which suggests the pathogenic role of IL10 in the disease.[44],[46],[47] IL-10 promotes B cell proliferation, antibody production and class switching.[44],[45] Reduction in renal impairments in an animal model of lupus disease after treatment with anti IL10 antibody shows the role of IL10 in renal pathology in SLE.[48] IFN-γ is another effective inflammatory cytokine in SLE.[49] Its serum levels have been reported to be elevated in SLE patients.[49] IFN-γ has also demonstrated a role in immune complex-mediated nephritis in the animal model.[49],[50] TGF-β is an anti-inflammatory cytokine and its serum titre has been reported to be lower in active SLE patients.[43],[44],[51] It suppresses B cells and inhibits the secretion of antibodies and serum levels of TGF-β are lower in SLE patients, probably due to high IL10 levels, which suppresses its production.[43] Inhibitory function of CD4+ CD25+ regulatory T cells (Tregs) is TGF-β dependent.[52] Disruption in Treg function is well known to be associated with autoimmune disorders. CTLA-4 has a direct relation with TGF-β function as it accelerates CTLA-4 expression.[53] CTLA-4 protein is necessary for TGF-β medicated Foxp3 induction and generation of Tregs.[52],[53] CTLA-4 enhances TGF-β signaling by suppressing Treg during cell-cell interaction.[54] Although, in the present study we did not observe any genotype-associated imbalances in these cytokines in north Indians [Table 3], supporting observations of the previous study in south Indians.[32]

Limitations of the study

As SLE is a relatively rare disorder, a large sample size could not be included in this study. Further studies in this field with a larger sample size and multicentre approach are required. Financial constraints can also limit the application of this test in the general population.


   Conclusions Top


A/A was the most common CTLA4 genotype in both SLE patients and healthy controls from North India. There was no statistically significant association between CTLA4 genotype and susceptibility to SLE in north Indians, contrary to the previous report in south Indians. Only the presence of generalised edema was found significantly associated with the A/G genotype.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published.

Acknowledgement

Funds from University Grants Commission (UGC) of India were utilized for this research.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3]



 

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