Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Association of Variants in the NF-kB Regulatory Pathway Loci with Systemic Lupus Erythematosus in Multiple Populations.

Wiley6,  Graham, Adrianto8,  Indra, Kelly5,  Jennifer A., Kaufman11,  Kenneth M., Anaya13,  Juan-Manuel, Networks7,  Marta E. Alarcón-Riquelme on Behalf of the BIOLUPUS and GENLES, Bae1,  Sang-Cheol

Hanyang University, Seoul, Republic of Korea
Oklahoma Medical Research Foundation; The University of Oklahoma Health Sciences Center
Oklahoma Medical Research Foundation; The University of Oklahoma Health Sciences Center; Oklahoma City VA Medical Center
Sanatorio Parque, Rosario, Argentina
Universidad del Rosario, Colombia
University of Alabama at Birmingham
University of California, Los Angeles
University of Chicago
University of Southern California Keck School of Medicine
US Department of Veterans Affairs Medical Center; Cincinnati Children's Hospital Medical Center
Wake Forest University Baptist Medical Center
Imperial College London
Wake Forest University Health Sciences
Instituto de Parasitologia y Biomedicina López-Neyra, CSIC, Granada, Spain
Medical University of South Carolina
Oklahoma Medical Research Foundation
Oklahoma Medical Research Foundation, Oklahoma City, OK
Oklahoma Medical Research Foundation; Center of Genomics and Oncological Research (GENyO), Granada, Spain
Oklahoma Medical Research Foundation; Co-First Authors
Oklahoma Medical Research Foundation; Co-Senior Authors

Background:

The transcription factor NF-kB is an important factor in inflammation and the immune response. Unrestrained NF-kB response has previously been associated with autoimmune disease, sepsis, and some cancers. It is therefore not surprising that NF-kB signaling is tightly regulated within the cell through a pathway of protein-protein interaction and post-translational protein modification. One key component of this pathway is the TNFAIP3 complex consisting of TNFAIP3, TNIP1, TNIP2, TAX1BP1, ITCH, and RNF11. This complex, along with the ubiquitin-conjugating enzyme UBE2L3, deactivates NF-kB pathway proteins through deubiquitation of K63 polyubiquitin chains and subsequently targets those proteins for degradation via K48 ubiquitination. Recent GWAS have revealed that genetic variants in the TNFAIP3, TNIP1, and UBE2L3 regions are associated with systemic lupus erythematosus (SLE) in subjects of European and Asian ancestry. SLE is an autoimmune disease characterized by loss of tolerance to self-antigens and dysregulated interferon responses. To further characterize and localize the effect of the TNFAIP3 regulatory complex, we genotyped and imputed single-nucleotide polymorphisms (SNPs) within and flanking TNIP1 on 5q33, TNIP2 on 4p16, UBE2L3 on 22q11, TAX1BP1 on 7p15 in multiple populations: African-Americans (1,569 cases/1,893 controls), Asians (1,328 cases/1,348 controls), Europeans (4,248 cases/3,818 controls), Gullah (155 cases/131 controls), and Hispanics enriched for Amerindian-European admixture (1,622 cases/887 controls).

Methods:

Using the Illumina iSelect system, we genotyped a total of 231 SNPs in and around those loci and 343 ancestry-informative markers (AIMs). We then imputed untyped SNPs at those loci using HapMap Phase III and 1000 Genomes Project data. We converted the posterior probabilities to the most likely genotypes with a threshold of 0.8 and removed imputed SNPs with less than 90% average certainty of the most probable genotypes. We assessed single marker association to SLE using logistic regression with sex and global ancestry adjustments under additive, dominant, and recessive genetic models.

Results:

We observed strong associations between SLE and multiple SNPs within TNIP1 in Europeans, Hispanics, African-Americans, and Asians (Pcombined=5 × 10E-8) with the strongest signal at rs7708392 (Pcombined=2.53 × 10E-19). We also identified strong associations within UBE2L3 in Europeans, Asians, African-Americans and Hispanics with the most significant association at rs7444 (Pcombined=1.25 × 10E-14).

Conclusions:

These results establish that variants within TNIP1 and UBE2L3 contribute to differential risk of SLE in multiple populations. Further functional studies will be required to determine the precise variant(s) influencing SLE risk.

To cite this abstract, please use the following information:
Wiley, Graham, Adrianto, Indra, Kelly, Jennifer A., Kaufman, Kenneth M., Anaya, Juan-Manuel, Networks, Marta E. Alarcón-Riquelme on Behalf of the BIOLUPUS and GENLES, et al; Association of Variants in the NF-kB Regulatory Pathway Loci with Systemic Lupus Erythematosus in Multiple Populations. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1586
DOI: 10.1002/art.29352

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