Elsevier

Gene

Volume 768, 5 February 2021, 145270
Gene

Research paper
Association of AIRE (rs2075876), but not CTLA4 (rs231775) polymorphisms with systemic lupus erythematosus

https://doi.org/10.1016/j.gene.2020.145270Get rights and content

Highlights

  • This study indicated that the AIRE (rs2075876) variant conferred protection against developing SLE disease.

  • This work revealed no apparent association with the CTLA4 (rs231775) variant and the development of SLE disease.

  • CTLA4 rs231775 (G/G) genotype observed significant difference with recurrent infection and hematuria.

Abstract

Background

The AIRE (rs2075876) and CTLA4 (rs231775) variants have a crucial function in controlling the negative selection and suppression of T lymphocytes. Numerous reports studied the association of AIRE and CTLA4 variants with different autoimmune disorders, but with inconclusive conclusions. The main purpose of this work is to evaluate the association of these two variants with SLE susceptibility among Egyptian patients.

Subjects and Methods

A total of 247 participants (100 SLE patients and 147 healthy controls) were enrolled in this case-controlled study. The genomic DNA of these dual variants was genotyped using the TaqMan genotyping method.

Results

The AIRE (rs2075876) variant conferred protection against developing SLE disease under allelic [A allele vs. G allele; OR = 0.16, 95%CI = 0.09–0.28], and dominant [GA + AA vs. GG; OR = 0.14, 95%CI = 0.05–0.34] models. Moreover, patients with AIRE rs2075876 (A/A) genotype revealed a statistically significant with lower levels of complement 3 (p-value = 0.007). Nonetheless, the CTLA4 (rs231775) variant was not associated with increased risk of SLE under all genetic association models (p-value > 0.05). However, CTLA4 rs231775 (G/G) genotype observed significant difference with recurrent infection and hematuria.

Conclusions

Our findings indicated that the AIRE (rs2075876) variant conferred protection against developing SLE disease, but not the CTLA4 (rs231775) variant.

Introduction

The systemic lupus erythematosus (SLE) is an inflammatory autoimmune illness with multiple immunological disturbances characterized by extreme complement stimulation and accumulation of autoantibodies against a diverse immune protein complex (Murphy and Isenberg, 2013, Al-Kholy et al., 2016). In this disorder, the immune system erroneously assaults multiple organ tissues throughout the body, particularly, skin, kidneys, brain, as well as joints, and predominantly infects child-bearing women compared with men with a reported proportion of (10:1) (Gurevitz et al., 2013, Murphy and Isenberg, 2013). The pathogenesis of SLE remains unclear, is thought that it originates from combinations of environmental and hereditary factors with some main symptoms ranging from molar rash into nephritis and arthritis with some hematological illness including anemia along with thrombocytopenia (Nath et al., 2004, Castro et al., 2008).

The autoimmune regulator (AIRE) gene is a transcription regulator that is essential for maintaining self-tolerance mechanism through controlling the negative selection of hyperreactivity T lymphocytes against autoantigens within the thymic medulla tissues (Yang et al., 2018, Montufar-Robles et al., 2019). The AIRE gene [OMIM number: 607358; other synonyms includes APECED and APS1] is located at chromosome 21q22.3 and comprised 14 exons that encoded 545 amino acids with a molecular mass of 57.7-kDa (Bruserud et al., 2016, Colobran et al., 2016). The imbalance of AIRE protein was associated with a syndrome recognized as autoimmune poly-endocrinopathy-candidiasis- ectodermal dystrophy (APECED) (Gardner et al., 2009). One of the putative polymorphisms within the AIRE gene is rs2075876 (c.653-387G > A, chr21:44289270) that plays a crucial function among different autoimmune disorders, including systemic lupus erythematosus (Montufar-Robles et al., 2019), rheumatoid arthritis (RA) (Terao et al., 2011, NH et al., 2020), and alopecia areata (Toraih et al., 2020). Furthermore, it was observed that the A allele of AIRE (rs2075876) was associated with an increased risk of rheumatoid arthritis compared with the G allele among different ethnic subjects (Bérczi et al., 2017). However, a single report was identified among Mexican subjects revealed no association between AIRE (rs2075876) and an increased risk of SLE (Montufar-Robles et al., 2019).

Cytotoxic T-lymphocyte associated protein 4 [CTLA4; OMIM number: 123890, other names involve CD152 and GSE], is a negative cytokine regulator that expressed on the exterior surface of activated T cells and performed a silencing signal against activated T-lymphocyte (Katkam et al., 2016, Babteen et al., 2020). It is linked with high-level binding with co-stimulating compounds; CD80 (B7-1) and CD86 (B7-2) on the outer surface of antigen-presenting cells (APCs) through its competition with the same binding locations of CD28, and hence exerted a critical role in T-lymphocyte tolerance (Elshazli et al., 2015, Liang et al., 2015). The CTLA4 gene is situated on chromosome 2q33.2 and contained 4 exons that encoded 223 amino acids with a molecular mass of 24.6-kDa (Megiorni et al., 2013). Numerous genetic variants were identified within the CTLA4 with the most common variant is c.49A > G (rs231775; p.Thr17Ala) at the first exon that displays a potential effect among diverse of autoimmune syndromes including systematic lupus erythematosus, rheumatoid arthritis, alopecia areata, and T1D (Taha Khalaf et al., 2011, Liu and Zhang, 2013, Megiorni et al., 2013, Elshazli et al., 2015, Li et al., 2016b). Recent studies revealed that CTLA4 rs231775 (GG genotype) conferred an increased risk of SLE among different ethnic populations, but with inconclusive conclusions (Lee et al., 2005, Liu and Zhang, 2013, Devaraju et al., 2014, Katkam et al., 2016). Consequently, for the first time, this study was designed to investigate the association between these important dual variants and the susceptibility, severity, and the clinic-laboratory markers of SLE among Egyptian subjects.

Section snippets

Study participants

This case-controlled study included a total of 247 participants [147 healthy controls and 100 SLE patients]. The newly diagnosed SLE patients were successively recruited from the Outpatient Clinics of the Rheumatology and Nephrology at the Suez Canal University Hospitals, Ismailia, Egypt. The diagnosis of SLE patients was carried out based on the new classification criteria of SLE proposed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) (Aringer

Baseline characteristics of the study population

The basic characteristics of SLE patients and healthy controls are illustrated in Table 1. A total of 147 healthy controls (136 females and 11 males) and 100 SLE patients (92 females and 8 males) were enrolled in the study. Their mean age was 35.8 ± 9.9 and 37.3 ± 9.7 years, respectively. There was no significant difference regarding their age at onset (p-value = 0.71) and sex (p-value = 0.88). Of the 100 SLE patients, 69% presented with early-onset (≤40 years old), and 38% had a positive

Discussion

Systemic lupus erythematosus is thought to be one of the most effective autoimmune disorders that threatened many organs within the body through its interfering with the normal function of the immune system (Chang et al., 2012, Abdel-Gawad et al., 2020). Recently, numerous reports investigated the potential effect of different genetic variants with the susceptibility for SLE within different populations (Ulker et al., 2009, Zhai et al., 2013, Montufar-Robles et al., 2019). The autoimmune

Conclusion

In conclusion, this work indicated a protection impact of the AIRE (rs2075876*A) allele with the development of SLE disease among Egyptian patients. On the contrary, the CTLA4 (rs231775*G) allele conferred no association with increased risk of SLE among the same population.

Data availability statement

The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.

CRediT authorship contribution statement

Saleh A. Alghamdi: Conceptualization, Methodology, Validation, Investigation, Writing - review & editing, Supervision. Shahad W. Kattan: Formal analysis, Methodology, Writing - review & editing. Eman A. Toraih: Data curation, Formal analysis, Methodology, Software, Validation, Visualization, Writing - review & editing. Majed Alrowaili: Methodology, Formal analysis, Writing - original draft, Data curation. Manal S. Fawzy: Methodology, Software, Formal analysis, Writing - original draft. Rami M.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

The authors thank all the participants who agree to be enrolled in the study. Also, many thanks extend to Taif University Researchers supporting project number (TURSP-2020/108), Taif, Saudi Arabia, for their support.

References (60)

  • S.K. Katkam et al.

    Association of CTLA4 exon-1 polymorphism with the tumor necrosis factor-α in the risk of systemic lupus erythematosus among South Indians

    Hum. Immunol.

    (2016)
  • J. Liang et al.

    Lack of association between cytotoxic T-lymphocyte antigen-4+49A/G polymorphism and psoriasis and vitiligo: A meta-analysis of case–control studies

    Gene

    (2015)
  • I. Montufar-Robles et al.

    The AIRE Ser196Ser synonymous variant is a risk factor for systemic lupus erythematosus

    Cell. Immunol.

    (2019)
  • S.K. Nath et al.

    Genetics of human systemic lupus erythematosus: the emerging picture

    Curr. Opin. Immunol.

    (2004)
  • T. Soga et al.

    Repressor element 1 silencing transcription factor /neuron-restrictive silencing factor (REST/NRSF) in social stress and depression

    Prog. Neuro-Psychopharmacol. Biol. Psychiatry

    (2021)
  • H.A. Abd El Daim et al.

    Unleash the association of mitochondrial uncoupling protein (UCP2) promoter variant (G-866A; rs659366) with obesity: stepping from a case-control study to a meta-analysis

    Biochem. Genet.

    (2020)
  • A.R. Abdel-Gawad et al.

    Association of microRNA 17 host gene variant (rs4284505) with susceptibility and severity of systemic lupus erythematosus

    Immun Inflamm Dis.

    (2020)
  • S. Ahmed et al.

    Association of CTLA-4 but not CD28 gene polymorphisms with systemic lupus erythematosus in the Japanese population

    Rheumatology (Oxford)

    (2001)
  • M. Aringer et al.

    2019 European League against rheumatism/american college of rheumatology classification criteria for systemic lupus erythematosus

    Arthritis Rheumatol

    (2019)
  • M. Barreto et al.

    Evidence for CTLA4 as a susceptibility gene for systemic lupus erythematosus

    Eur. J. Hum. Genet.

    (2004)
  • B. Bérczi et al.

    Association between AIRE gene polymorphism and rheumatoid arthritis: a systematic review and meta-analysis of case-control studies

    Sci. Rep.

    (2017)
  • C. Bombardier et al.

    Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE

    Arthritis Rheum.

    (1992)
  • W.W. Chang et al.

    Association between CTLA-4 exon-1 +49A/G polymorphism and systemic lupus erythematosus: an updated analysis

    Mol. Biol. Rep.

    (2012)
  • K.H. Chua et al.

    Study of the CTLA-4 gene polymorphisms in systemic lupus erythematosus (SLE) samples from Malaysia

    Ann. Hum. Biol.

    (2010)
  • P. Devaraju et al.

    The CTLA4 +49 A/G (rs231775) polymorphism influences susceptibility to SLE in South Indian Tamils

    Tissue Antigens

    (2014)
  • S. Dong et al.

    Predicting functional variants in enhancer and promoter elements using RegulomeDB

    Hum. Mutat.

    (2019)
  • R.M. Elshazli et al.

    Genetic polymorphisms of ACE I/D, IL-1beta G > A and IL-4 VNTR among Egyptian subjects with rheumatoid arthritis

    Arch. Physiol. Biochem.

    (2019)
  • D. Eriksson et al.

    Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison's disease in Sweden

    Sci. Rep.

    (2018)
  • J.R. García-Lozano et al.

    Association of the AIRE gene with susceptibility to rheumatoid arthritis in a European population: a case control study

    Arthritis Res Ther

    (2013)
  • S.L. Gurevitz et al.

    Systemic lupus erythematosus: a review of the disease and treatment options

    Consult. Pharm.

    (2013)
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