Influence of Polymorphism −308 G/A of the Tnf-α Gene on High Mobility Group Box-1 Protein in Rheumatoid and Spondylo-Arthritis Patients

Abstract

Single nucleotide polymorphism (SNP) in the human Tumor Necrosis Factor-α(TNF-α) gene promoter, the −308 G/A variant, has been associated with increased TNF-α levels that may amplify the severity of rheumatoid arthritis (RA) and a poor responsiveness to TNF-α blockade therapy. High mobility group box protein (HMGB-1) is a pro-inflammatory cytokine that plays a pivotal role in the pathogenesis of RA and may be an original target of therapy. The aim of this study is to investigate whether the −308 G/A variant of the TNF-α gene is associated with altered expression of HMBG-1. A total of 110 consecutive patients with rheumatoid arthritis and spondylo-arthritis (ankylosing spondylitis, psoriatic arthritis and spondylitis associated with inflammatory bowel disease) referring to the Rheumatology Unit of Messina University Hospital were enrolled. Patients were genotyped for the −308 TNF-α gene promoter polymorphism. Clinical status was also assessed. HMGB-1 and TNF-α mRNA(Real Time PCR) from total blood and plasmatic HMGB-1 (Western Blot analysis) and TNF-α (ELISA) protein were also evaluated. Irrespective of the underlying disease, patients carrying the G/A genotype showed enhanced HMGB-1 and TNF-α mRNA levels and increased circulating concentration of the inflammatory cytokines when compared to patients with G/G genotype. The data suggest that subjects carrying the TNF-α −308G/A genotype have enhanced expression of HMGB-1 protein that may explain, at least in part, the increased severity of the disease.