Tumour Necrosis Factor α Gene Promoter and its Role in Rheumatoid Arthritis Outcome and Pharmacogenetics

Rheumatoid arthritis (RA) is a chronic inflammatory disease which affects approximately 1% of the world population. A considerable effort has been put into understanding the genetic factors associated with this complex disease. Sequencing of the human genome has opened new prospects for the detection of genetic variants associated with increased susceptibility, poor prognosis and inadequate response to therapy. One of the most promising candidate genes is TNFα, not only due to its pivotal role in the inflammatory process, but also because anti-TNFα drugs have become the golden standard in RA therapy. Of particular interest are the highly abundant single nucleotide polymorphisms (SNPs), particularly when they occur in regulatory regions, such as the promoter of the gene, upregulating or downregulating the production of TNFα by changing the affinity of transcription factors to their binding sites. In this review, we address the influence exerted by TNFα gene promoter SNPs in RA, focusing particularly on their effect on TNFα production. Subsequently, we review the results of association studies addressing the influence of these polymorphisms on RA susceptibility, prognosis and response to therapy, with special concern on specific anti-TNFα drugs.