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African-derived genetic polymorphisms in TNFAIP3 mediate risk for autoimmunity
James P Lodolce1, Lauren E Kolodziej, Lesley Rhee
1Department of Medicine, University of Chicago, Chicago, IL 60612, USA.
Journal of Immunology (Baltimore, Md. : 1950)
|May 21, 2010
Summary
TNFAIP3 gene variants are linked to autoimmune diseases like SLE in African Americans. A specific variant (A125V) protects against SLE but increases inflammatory bowel disease risk, altering protein function.
Area of Science:
- Genetics
- Immunology
- Molecular Biology
Background:
- TNF alpha-induced protein 3 (TNFAIP3) is a key negative regulator of inflammation.
- TNFAIP3 genetic variations are associated with autoimmune disorders in European populations.
- Two coding polymorphisms, F127C and A125V, exist in the TNFAIP3 deubiquitinating (DUB) domain.
Purpose of the Study:
- Investigate the association of TNFAIP3 coding variants and polymorphisms with systemic lupus erythematosus (SLE) in African Americans.
- Identify novel risk and protective haplotypes within the TNFAIP3 locus in this cohort.
- Determine the functional impact of the A125V variant on TNFAIP3 deubiquitinating activity.
Main Methods:
- Case-control study design involving African-American SLE patients.
- Genotyping of coding variants (F127C, A125V) and tagging polymorphisms in TNFAIP3.
- Functional assays to assess the deubiquitinating activity of TNFAIP3 variants.
- Computer modeling to analyze the structural impact of amino acid changes.
Main Results:
- A novel African-derived TNFAIP3 risk haplotype was identified (OR=1.6, p=0.006).
- The A125V variant was part of a rare protective haplotype for SLE (OR=0.31, p=0.027).
- A125V demonstrated altered DUB activity and a greater structural impact on the DUB domain compared to F127C.
- A125V was associated with SLE protection but increased risk for inflammatory bowel disease.
Conclusions:
- TNFAIP3 polymorphisms are associated with autoimmunity in African Americans.
- The A125V variant has differential effects on SLE and inflammatory bowel disease susceptibility.
- Functional and structural alterations of TNFAIP3 by A125V contribute to autoimmune disease risk.
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