The proinflammatory cytokine TNF-alpha -308 AA genotype is associated with polyglandular autoimmunity

Data regarding polymorphisms of immunoregulatory genes in polyglandular autoimmunity (PGA) are lacking. We have analyzed whether the polymorphism of the proinflammatory cytokine gene TNF-alpha; -308 and mutations of the autoimmune regulator (AIRE) gene were associated with PGA in adults. Sixty-seven patients with PGA and 209 healthy controls were genotyped by multiplex minisequencing with capillary electrophoresis on an ABI PRISM-310 genetic analyzer. HLA DRB1 typing was performed using polymerase-chain-reaction-amplified DNA hybridized with sequence-specific-oligonucleotide probes (PCR-SSO). The TNF-alpha; -308*A allele occurred more frequently in patients (0.269) than in controls (0.163, P = 0.008, P(c) = 0.016). Also, TNF-alpha; -308*A carriers were more frequent in patients than controls (47.8% vs. 31.1%, OR = 1.89, 95%CI = 1.19-3.00). The frequency of the AA genotype was increased in PGA (P = 0.014, P(c) = 0.042). PGA patients with autoimmune thyroid disease and the TNF-alpha; -308 AA genotype showed the highest prevalence of thyroid autoantibodies (TPO, P = 0.04; Tg, P = 0.003). HLA-DRB1*03 and TNF-alpha; -308*A alleles were strongly associated in patients with PGA (87.5%, P(c) < 0.00001). The AIRE R257X and 13bpdel mutations were not observed in patients with PGA. The association of TNF-alpha; -308*A with PGA might be directly or indirectly due to the association with HLA-DRB1*03.