RESUMEN
Abnormal expression of the costimulatory molecules cytotoxic T-lymphocyte antigen 4 (CTLA-4), CD28, and inducible co-stimulator (ICOS) leads to disturbances of immune response and an increased risk of cancer. An extended study was undertaken to evaluate the association among the polymorphisms CTLA-4c.49A>G, CTLA-4g.319C>T, CTLA-4g.*642AT(8_33), CD28c.17+3T>C, and ICOSc.1554+4GT(8_15) and susceptibility to B-cell chronic lymphocytic leukemia (B-CLL) in the Polish population. The study revealed increased frequency of the CTLA-4g.319C>T [T] allele and the CTLA-4g.319C>T [T] phenotype in B-CLL patients compared with healthy controls (p = 0.003, odds ratio [OR] = 1.73; and p = 0.009, OR = 1.74, respectively). The presence of the CD28c.17+3T>C [C] allele and the CD28c.17+3T>C [C] phenotype increased the OR of B-CLL to 1.59 (p = 0.007) and 1.74 (p = 0.007), respectively. Either CTLA-4g.319C>T or CD28c.17+3T>C was associated with time to Rai stage progression. The distributions of the alleles and genotypes of the ICOS gene significantly differed between patients and controls (p = 0.0009 and p = 0.006, respectively). Individuals possessing short alleles were 2.02 times more prone to B-CLL than others (p = 0.001), whereas carriers of long alleles were protected from B-CLL (p = 0.02, OR = 0.62). The haplotype association study and multivariate analysis confirmed the association of CTLA-4g.319C>T and ICOSc.1554+4GT(8_15) gene polymorphisms with B-CLL. The polymorphic sites CTLA-4c.49A>G and CTLA-4g.*642AT(8_33) did not correlate with B-CLL. Our results are the first in the literature to report that gene polymorphism of the costimulatory molecules CTLA-4, CD28, and ICOS contributes to susceptibility to B-CLL.
Asunto(s)
Antígenos CD/genética , Antígenos de Diferenciación de Linfocitos T/genética , Antígenos de Diferenciación/genética , Antígenos CD28/genética , Leucemia Linfocítica Crónica de Células B/genética , Polimorfismo Genético/genética , Anciano , Alelos , Antígeno CTLA-4 , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética , Genotipo , Haplotipos , Humanos , Proteína Coestimuladora de Linfocitos T Inducibles , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Análisis Multivariante , Fenotipo , PoloniaAsunto(s)
Antígenos CD19/sangre , Antígenos de Diferenciación/sangre , Linfocitos B/inmunología , Ciclo Celular/inmunología , Leucemia de Células B/inmunología , Antígenos CD/sangre , Antígenos de Diferenciación/genética , Linfocitos B/patología , Antígenos CD5/sangre , Antígeno CTLA-4 , Progresión de la Enfermedad , Exones , Femenino , Genotipo , Humanos , Fragmentos Fc de Inmunoglobulinas/sangre , Fragmentos Fc de Inmunoglobulinas/genética , Leucemia de Células B/sangre , Masculino , Regiones Promotoras Genéticas , Valores de Referencia , Linfocitos T Citotóxicos/inmunologíaRESUMEN
OBJECTIVES: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system which is widely believed to have a T-cell-mediated etiology. The cytotoxic T-lymphocyte antigen-4 (CTLA-4) antigen molecule plays a key role in the downregulation of T-cell responses. To examine the genetic association of the CTLA-4 gene locus with MS, we analyzed an exon 1 (A49G) transition. MATERIAL AND METHODS: One hundred and fifty-two MS patients and 154 controls were examined. The A/G transition was genotyped by a polymerase chain reaction followed by labeling with a SNaPshot kit and detection using a capillary genetic analyzer. RESULTS: The genotype, allele and phenotype frequencies did not differ significantly between MS patients and controls. Those MS patients with AA and AG genotypes had 4.36 times greater risk of progressing from the relapsing-remitting to the secondary progressive form of the disease than those with the GG genotype. CONCLUSION: The results of our study indicate that CTLA-4 (A49G) exon 1 polymorphism is associated with MS progression.