RESUMEN
Graves' disease (GD) is the commonest cause of hyperthyroidism in populations with adequate iodine intake. It results from an abnormality in the immune system, which produces unique antibodies causing over production of thyroid hormones and glandular hyperplasia in individuals with genetic susceptibility. The Cytotoxic Lymphocyte Associated Antigen-4 (CTLA4) gene product serves the important function of immunomodulation, thereby helping in maintenance of peripheral self-tolerance. Studies on the association of the CTLA4 SNPs with GD have shown variations in the results from different populations. Since no such study has been carried out in ethnic Kashmiri population, we aimed to study a possible association of the CTLA4 SNPs (+49 A/G, -318C/T, CT 60 A/G and -1661 A/G) with GD. A total of 285 individuals (135 patients with GD and 150 healthy individuals) were genotyped using PCR-RFLP method and the results showed statistically significant differences in genotypic and allelic frequencies of cases and controls forâ¯+â¯49 A/G SNP (p=<0.001; ORâ¯=â¯5.14; CIâ¯=â¯2.17-12.19) and CT 60 A/G SNP (pâ¯=â¯<â¯0.001; ORâ¯=â¯6.9; CIâ¯=â¯2.8-16.6), while -318C/T and -1661 A/G SNPs showed no significant association. We also studied the mRNA expression of the CTLA4 in patients with GD and healthy individuals by Real-Time PCR and found a decreased expression of the CTLA4 mRNA in PBMCs of patients with GD as compared to healthy controls with a -3.71-fold change. We conclude that the CTLA4â¯+â¯49 A/G and CT 60 A/G SNPs have a significant association with the risk of GD development in Kashmiri population and CTLA4 mRNA expression is significantly decreased in GD.
Asunto(s)
Antígeno CTLA-4/genética , Predisposición Genética a la Enfermedad/genética , Enfermedad de Graves/genética , Autotolerancia/genética , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes/genética , Genotipo , Enfermedad de Graves/inmunología , Humanos , India/etnología , Masculino , Persona de Mediana Edad , Polimorfismo de Longitud del Fragmento de Restricción/genética , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Autotolerancia/inmunología , Hormonas Tiroideas/biosíntesis , Adulto JovenRESUMEN
BACKGROUND: Graves' disease (GD) is a multifactorial autoimmune disease with contribution from both genetic and epigenetic factors in its causation. Association of genetic factors and GD has been extensively studied. Gene "protein tyrosine phosphatase nonreceptor 22" (PTPN22) is an important immunoregulatory gene preventing hyper responsiveness of T cells by negatively regulating their signal transduction. Association of single-nucleotide polymorphism (SNP) 1858 C/T within PTPN22 with some autoimmune diseases has been described. METHODS: We aimed to analyze whether 1858 C/T SNP of PTPN22 gene has any association with GD in Kashmiri population. Polymerase chain reaction-restriction fragment length polymorphism was performed for genotyping 1858 C/T SNP in 135 patients with GD and 150 age- and gender-matched healthy controls. RESULTS: Among the patients with GD, the frequencies of PTPN22 1858 CC, CT, and TT genotypes were 97.7, 2.2, and 0%, respectively, whereas in healthy controls the frequencies of CC, CT genotypes were 100 and 0%, respectively. No significant association was found between PTPN22 1858 C/T SNP and patients with GD. CONCLUSION: GD is not associated with PTPN22 1858 C/T SNP in Kashmiri population. Furthermore, 1858 C/T SNP in PTPN22 gene could be a part of variation in different ethnic populations across the globe.