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