title: Association of CTLA-4 polymorphisms and clinical-immunologic characteristics at onset of type 1 diabetes mellitus in children.
abstract: CTLA-4 is a homeostatic regulator of T cell activation and is believed to play a critical role in immune tolerance. Polymorphisms in the CTLA-4 promoter (-318C/T) and in exon 1 (+49 A/G) were analyzed in 300 Chilean patients with type 1 diabetes mellitus (T1D) and 310 healthy children by polymerase chain reaction-restriction fragment length polymorphism. The effect of CTLA-4 allele and haplotype frequencies on the interferon-gamma, tumor necrosis factor-alpha, and transforming growth factor-beta(1) levels and the presence in serum of GAD65 and IA-2 autoantibodies at the onset of T1D was evaluated. The distribution of the CTLA-4 allele and genotype frequencies was found to be similar in patients and control children. However, among the T1D patients' carriers of GG genotype on CTLA-4 gene a higher frequency of anti-GAD65 autoantibodies (87.2%) was observed. On the other hand, higher ketoacidosis at onset, younger age at onset, and higher levels of tumor necrosis factor-alpha and interferon-gamma were observed in T1D patients carriers of G allele in comparison with the carriers of AA genotype. In conclusion, the result of this study showed that CTLA-4 +49 A/G and -318 C/T polymorphisms were not linked with a higher genetic risk for T1D. However, the presence of a GG genotype or G allele dosage was associated with a younger age of onset, higher prevalence of ketoacidosis at the moment of diagnosis and positive anti-GAD65 serum autoantibodies.
authors.affiliation: Genetic Epidemiology Laboratory, Nutrition and Food Technology Institute (INTA), University of Chile, Santiago, Chile.
authors.forename: Iván
authors.initials: I
authors.lastname: Balic
authors.forename: Bárbara
authors.initials: B
authors.lastname: Angel
authors.forename: Ethel
authors.initials: E
authors.lastname: Codner
authors.forename: Elena
authors.initials: E
authors.lastname: Carrasco
authors.forename: Francisco
authors.initials: F
authors.lastname: Pérez-Bravo
mesh_terms: D000293:Adolescent; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood; D060908:CTLA-4 Antigen; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006650:Histocompatibility Testing; D006801:Humans; D007223:Infant; D008297:Male; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide
chemical_list: D015703:Antigens, CD; D001323:Autoantibodies; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines