Association of Cytotoxic T-Lymphocyte Antigen-4 Gene Polymorphism with Type 1 Diabetes Mellitus: In silico Analysis of Biological Features of CTLA-4 Protein on Ethiopian Population

Abstract

Background: T1DM is a chronic organ-specific T-cell-mediated autoimmune disease characterized by the selective destruction of βcells in the islets of Langerhans, resulting in insulin deficiency and hyperglycemia. Genes for cytotoxic T lymphocyte-associated antigen 4 have been hypothesized as possible contender genes for T1DM vulnerability. However, it has not been studied in the Ethiopian population yet. Objective: The aim of the study was to investigate CTLA-4 exon 1 was linked to A49G polymorphism with T1DM and its biological features of CTLA-4 among T1DM patients, in Ethiopia. Methods: A case-control study was done from December 2019 to March 2020 on 210 study participants (105 T1DM patients and 105 healthy controls). Polymerase Chain Reaction amplification with forward and reverse primers was followed by restriction fragment length polymorphism and gel electrophoresis to determine gene polymorphism. Bioinformatics data of SNP was retrieved from National Centers for Biotechnology Information databases. The chi-square test and logistic regression were used. Statistical significance was defined as a P-value of less than 0.05. Results:The CTLA-4 (+A49G) gene polymorphism was observed on 56 (26.7%) study participants, 39 (18.57%) of T1DM patients, and 17 (0.08%) were controls. In T1DM and controls, the frequency of the A allele was 73.3% and 89.5%, while the G allele was 26.7% and 10.5%, respectively. The G allele was found to be associated with T1DM (OR=3.1; 95% CI, 1.82 −5.32; P=0.001). Statistical analysis revealed an association between the likelihood of T1DM and GG genotype of the CTLA-4 (+A49G) gene polymorphism (OR=3.11; 95% CI, 1.37-10.90; P=0.01). Further in silico analyzed the SNP to assess its biological features. Conclusion:The study showed as CTLA-4 (+A49G) gene polymorphism is linked with T1DM in the Ethiopian population.

Evaluation of CTLA-4 (+ 49A/G) polymorphism association with rheumatoid arthritis in Egyptian patients

“…In this polymorphism, the adenine base is substituted by a guanine base resulting in the translation of an alanine amino acid instead of a threonine amino acid at the 17th codon of the leader peptide. 19 The GG genotype has been found to result in decreased inhibitory function of CTLA4 on the proliferation of T cells after exposure to stimulation by an allogenic cell line. 20 Moreover, the +49G polymorphism was found to result in incomplete glycosylation of the leader peptide th s a tering the mo ec e's processing in the endoplasmic reticulum and resulting in lower surface levels of CTLA-4 in transfected cells.…”

Evidence of Association between CTLA-4 Gene Polymorphisms and Colorectal Cancers in Saudi Patients

“…This CTLA-4 genetic variants in the exon 1 is a missense variation leading to a threonine to alanine substitution at codon 17 (Thr17Ala). Functional analysis has shown that this polymorphism result in an inefficient CTLA-4 glycosylation and reduced cell surface expression and consequently disruption of the balance CD28 and CTLA-4 interactions with B7-1/2 [ 48 , 49 ]. In various case reports or systematic review, the +49A > G variant was connected to increased risks to many cancer diseases, including head and neck cancer, breast cancer, lung cancer, esophageal, liver cancer and pancreatic cancer [ 27 , 50 , 51 , 52 ].…”

A Concerted Vision to Advance the Knowledge of Diabetes Mellitus Related to Immune Checkpoint Inhibitors

“…Additionally, it may consolidate the postulated background of the predilection of anti-PD-1/anti-PD-L1 mAbs for the development of irDM and may illuminate the emerging, yet inconsistent, association of the CTLA-4 gene and its polymorphisms with genetic susceptibility to T1DM. If the latter association is established, it may launch a new field of research on the uncertain role of anti-CTLA-4 mAbs in the development of irT1DM [131][132][133].…”