[Polymorphism of TNF-alpha in autoimmunity and tuberculosis]

Tumor necrosis factor alpha (TNF-alpha) has been incriminated in several autoimmune and infectious diseases. The influence of TNF-alpha -308 polymorphism was examined in patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), primary Sjögren's syndrome (pSS) and tuberculosis. Genomic DNA from patients with RA (N=165), SLE (N=118), pSS (N=67), tuberculosis (N=138), as well as ethnic-matched controls (N=419) were characterized for the TNF-alpha -308 genetic polymorphism using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. TNF2 allele was associated with RA (OR: 1.6, C.I.95% 1.2-2.3, p=0.008), SLE (OR: 2.3, 95%C.I. 1.6-3.3, p<0.0001), and pSS (OR: 2.7, 95%C.I. 1.7-4.1, p<0.0001). TNF1 was associated with tuberculosis (OR: 1.9, 95%C.I. 1.2-3.1, p=0.02). TNF1/TNF2 heterozygosity was associated with susceptibility for RA (OR: 1.7, 95%C.I. 1.2-2.6, p=0.01), SLE (OR: 3, 95%C.I. 2-4.7, p<0.0001), and pSS (OR: 3.8, 95%C.I. 2.2-6.5, p<0.0001). The homozygous state TNF1/TNF1 was protective for autoimmunity (OR<0.6, p<0.01). In contrast, the TNF1/TNF2 genotype was a protective factor for tuberculosis (OR 0.5, 95%C.I. 0.3-0.9, p=0.02) whereas TNF1/TNF1 homozygosity was associated with susceptibility (OR: 2, 95%C.I. 1.2-3.4, p=0.02). These results indicate that TNF2 is a common susceptibility allele for autoimmune rheumatic diseases and a protective one for tuberculosis. In addition, the data point towards a genetic selection in our population that might be maintained through dominant selection (heterozygote advantage) to infection by M. tuberculosis but susceptible to autoimmunity.