Single-nucleotide polymorphisms (SNPs) are the most common genetic variations and occur at a frequency of approximately 1 in 1000 bp throughout the genome. The −308 TNF SNP is a mutation that affects the promoter region of the TNF gene. It defines the TNF1 and TNF2 alleles, determining low and high levels of TNF expression, respectively. The presence of the TNF2 allele has also been linked to increased susceptibility to and severity in a variety of autoimmune and inflammatory disorders, including RA, systemic lupus erythematosus, and ankylosing spondylitis. Studies on the functional significance of −308 SNP have detected higher levels of TNF production by cells from TNF2-carrying individuals than cells from TNF1 individuals. This difference does not appear to be due to other genes lying within the MHC region. Since the presence of the TNF2 allele may increase the host's resistance to local infection, by increasing local production of TNF at the infection site, we may suggest that such a mutation has emerged as a selective advantage to carriers of the TNF2 allele. This hypothesis may prove itself by observing the high incidence of tuberculosis and other infectious processes in those patients treated with anti-TNF therapy.
Since the human lifespan has increased, the persistence of the TNF2 allele at high frequency in the population now confers what appears to be a marked survival disadvantage. As a result of the disregulation of the immune system, the genetically-predisposed host expresses larger amounts of TNF, leading to chronic inflammatory processes and autoimmune diseases, currently more prevalent. We suggest that RA, a relatively new and increasingly frequent disease, is favored by the presence of the −308 TNF promoter polymorphism, responsible for increased TNF production.