Single nucleotide polymorphisms at the TNFAIP3/A20 locus and susceptibility/resistance to inflammatory and autoimmune diseases.

The anti-inflammatory and immune regulatory functions of the ubiquitin-editing and NF-kappaB inhibitory protein A20 are well documented in vitro, and in multiple animal models. The high rank held by A20 in the cell's physiologic anti-inflammatory defense mechanisms is highlighted by the striking phenotype of A20 knockout mice, characterized by cachexia, multi-organ failure, and premature death. Even partial depletion of A20, as in A20 heterozygous mice, significantly alters NF-kappaB activation in response to pro-inflammatory activators, even though these mice are phenotypically unremarkable at baseline. A recent burst of genome wide association studies (GWAS), fueled by advances in genomic technologies and analysis tools, uncovered associations between single nucleotide polymorphisms (SNPs) at the TNFAIP3/A20 gene locus and multiple autoimmune and inflammatory diseases in humans. Interestingly, some of these studies emphasized significant associations between TNFAIP3/A20 SNPs imparting decreased expression or loss of NF-kappaB inhibitory function, and susceptibility to systemic lupus erythematosus (SLE) and coronary artery disease (CAD). These clinical data phenocopy partial loss of A20 in mouse models of inflammatory diseases, thereby incriminating TNFAIP3/A20 deficiency as a pathogenic culprit in autoimmune and inflammatory diseases. In this chapter, we undertook a thorough review of studies that explored association between TNFAIP3/A20 SNPs and human autoimmune and inflammatory diseases. Beyond the prognostic value of TNFAIP3/ A20 SNPs for assessing disease risk, their implication in the pathogenic processes of these maladies prompts the pursuit of A20-targeted therapies for disease prevention/treatment in patients harboring susceptibility haplotypes.