Tumour necrosis factor-alpha (TNF-α), lymhotoxin-alpha (LT-α), and tumour necrosis factor receptor 2 (TNFR2) gene polymorphisms and clinical course of sarcoidosis

Granulomatous inflammation, a feature of sarcoidosis, is associated with the production of several proinflammatory cytokines. TNF-α and LT-α are two such cytokines with gene loci located near the HLA-B locus on chromosome 6. TNFR2 is a high affinity receptor which is involved in mediating the diverse cellular and biological effects of TNF-α and LT-α. The TNFR2 gene is located on chromosome 1p36.2. The aim of this study therefore was to determine whether variation in the genes encoding for TNF-α, LT-α and TNFR2 contribute to disease susceptibility and outcome in sarcoidosis. Genetic variants were identified using the Polymerase Chain Reaction with Sequence Specific Primers (PCR-SSP) for both patients (n=126) and healthy controls (n=201). An analysis of radiographic records at four years from diagnosis allowed the patient group to be stratified into mild, moderate and severe cases. TNFR2, TNFα, and LTα phenotype and genotype frequencies did not differ significantly between the sarcoidosis patients and controls. A TNFR2 exon 6 variant (the G at nt +676), however, was found to be significantly associated with protection against severe disease outcome, occurring in 12.5% of severe cases versus 28.8% of mild cases (p=0.01). This variant is associated with an amino acid change suggesting a functional consequence for this alteration in sarcoidosis patients. We hypothesize therefore that the TNFR2 exon 6 variant with its subsequent amino acid change is a strong candidate gene for disease progression in sarcoidosis.