African-derived genetic polymorphisms in TNFAIP3 mediate risk for autoimmunity.

Publication Type:

Journal Article


Journal of immunology (Baltimore, Md. : 1950), Volume 184, Issue 12, p.7001-9 (2010)


African Americansdigestive disease, digestive deseases Autoimmunitydigestive disease, digestive deseases Case-Control Studiesdigestive disease, digestive deseases Genetic Predisposition to Diseasedigestive disease, digestive deseases Genome-Wide Association Studydigestive disease, digestive deseases Humansdigestive disease, digestive deseases Immunoblottingdigestive disease, digestive deseases Immunoprecipitationdigestive disease, digestive deseases Intracellular Signaling Peptides and Proteinsdigestive disease, digestive deseases Lupus Erythematosus, Systemicdigestive disease, digestive deseases Nuclear Proteinsdigestive disease, digestive deseases Polymerase Chain Reactiondigestive disease, digestive deseases Polymorphism, Geneticdigestive disease, digestive deseases Polymorphism, Single Nucleotidedigestive disease, digestive deseases Protein Structure, Quaternarydigestive disease, digestive deseases Transfection


The TNF alpha-induced protein 3 (TNFAIP3) is an ubiquitin-modifying enzyme and an essential negative regulator of inflammation. Genome-wide association studies have implicated the TNFAIP3 locus in susceptibility to autoimmune disorders in European cohorts, including rheumatoid arthritis, coronary artery disease, psoriasis, celiac disease, type 1 diabetes, inflammatory bowel disease, and systemic lupus erythematosus (SLE). There are two nonsynonymous coding polymorphisms in the deubiquitinating (DUB) domain of TNFAIP3: F127C, which is in high-linkage disequilibrium with reported SLE-risk variants, and A125V, which has not been previously studied. We conducted a case-control study in African-American SLE patients using these coding variants, along with tagging polymorphisms in TNFAIP3, and identified a novel African-derived risk haplotype that is distinct from previously reported risk variants (odds ratio=1.6, p=0.006). In addition, a rare protective haplotype was defined by A125V (odds ratio=0.31, p=0.027). Although A125V was associated with protection from SLE, surprisingly the same allele was associated with increased risk of inflammatory bowel disease. We tested the functional activity of nonsynonymous coding polymorphisms within TNFAIP3, and found that the A125V coding-change variant alters the DUB activity of the protein. Finally, we used computer modeling to depict how the A125V amino acid change in TNFAIP3 may affect the three-dimensional structure of the DUB domain to a greater extent than F127C. This is the first report of an association between TNFAIP3 polymorphisms and autoimmunity in African-Americans.