title: Association of single nucleotide polymorphisms in cytotoxic T-lymphocyte antigen 4 and susceptibility to autoimmune type 1 diabetes in Tunisians.
abstract: In addition to HLA and insulin genes, the costimulatory molecule CTLA-4 gene is a confirmed type 1 diabetes (T1D) susceptibility gene. Previous studies investigated the association of CTLA-4 genetic variants with the risk of T1D, but with inconclusive findings. Here, we tested the contributions of common CTLA-4 gene variants to T1D susceptibility in Tunisian patients and control subjects. The study subjects comprised 228 T1D patients (47.8% females) and 193 unrelated healthy controls (45.6% females). Genotyping for CTLA-4 CT60A/G (rs3087243), +49A/G (rs231775), and -318C/T (rs5742909) was performed by PCR-restriction fragment length polymorphism (RFLP) analysis. The minor-allele frequencies (MAF) for the three CTLA-4 variants were significantly higher in T1D patients, and significantly higher frequencies of homozygous +49G/G and homozygous CT60G/G genotypes were seen in patients, which was confirmed by univariate regression analysis (taking the homozygous wild type as a reference). Of the eight possible three-locus CTLA-4 haplotypes (+49A/G, -318C/T, and CT60A/G) identified, multivariate regression analysis confirmed the positive association of ACG (odds ratio [OR], 1.93; 95% confidence interval [CI], 1.26 to 2.94), GCG (OR, 2.40; 95% CI, 1.11 to 5.21), and GTA (OR, 4.67; 95% CI, 1.52 to 14.39) haplotypes with T1D, after confounding variables were adjusted for. Our results indicate that CTLA-4 gene variants are associated with increased T1D susceptibility in Tunisian patients, further supporting a central role for altered T-cell costimulation in T1D pathogenesis.
authors.affiliation: Research Unit of Hematological and Autoimmune Diseases, Faculty of Pharmacy, University of Monastir, Monastir, Tunisia.
authors.forename: Jihen
authors.initials: J
authors.lastname: Benmansour
authors.forename: Mouna
authors.initials: M
authors.lastname: Stayoussef
authors.forename: Fayza A
authors.initials: FA
authors.lastname: Al-Jenaidi
authors.forename: Mansoor H
authors.initials: MH
authors.lastname: Rajab
authors.forename: Chiheb B
authors.initials: CB
authors.lastname: Rayana
authors.forename: Hichem B
authors.initials: HB
authors.lastname: Said
authors.forename: Touhami
authors.initials: T
authors.lastname: Mahjoub
authors.forename: Wassim Y
authors.initials: WY
authors.lastname: Almawi
mesh_terms: D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000235:genetics*; D060908:CTLA-4 Antigen; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D004198:Disease Susceptibility; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D014416:Tunisia; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human