Polimorfismo +49 A/G del gen del antígeno 4 del linfocito T citotóxico (CTLA-4) en la diabetes tipo 1: Asociación con el perfil de anticuerpos y citoquinas

Abstract

Background: Cytotoxic T lymphocyte associated antigen 4 (CTLA-4) has been one of the non HLA genes more commonly studied in type 1 diabetes mellitus (TID). CTLA-4 is a co-stimulation protein that has a key role in the negative regulation of T cells and is related with a functional cytokine imbalance, generating a T helper (Th) 1 over Th2 dominance. Aim: To analyze the association of +49 A/G polymorphism of CTLA-4 and its relationship with autoantibodies and cytokine expression in recently diagnosed TID patients. Patients and Methods: CTLA-4 genetic variants and auto-antibody levels were studied in 260 children with TID and 255 healthy children matched by age and gender. +49 A/G polymorphism of CTLA-4 was studied by polymerase chain reaction and restriction fragment polymorphism (PCR-RFLP). Autoantibody levels were measured by conventional ELISA. A panel of 60 cytokines was studied simultaneously by serum array analysis in 15 TID and 15 healthy controls stratified according CTLA-4 genotype. Results: The +49 A/G genetic frequency was similar in TID cases and healthy children. A positive anti-GAD65 and anti-IA-2 level was observed in 67.3% of TID group. This percentage was increased among GG carriers (79.4% to GAD65 and 70.6% to IA-2). Finally, TID patients carrying this genotype showed a high expression of interleukin 2, 10, tumor necrosis factor alpha and interferon gamma. Conclusions: The +49 A/G polymorphism of CTLA-4 was similar in diabetic and control children. Among patients with TID and carriers of GG genotype, a higher frequency of anti-GAD65 and a preferential Th1 cytokine expression profile was observed.