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 TNFAIP3 Region with Systemic Lupus Erythematosus in a Multi-Ethnic Study.

Adrianto5,  Indra, Lessard8,  Christopher J., Kaufman9,  Kenneth M., Anaya12,  Juan-Manuel, Networks6,  Marta E. Alarcón-Riquelme on Behalf of the BIOLUPUS and GENLES, Bae1,  Sang-Cheol, PROFILE13,  Elizabeth E. Brown for

Hanyang University, Seoul, Republic of Korea
Sanatorio Parque, Rosario, Argentina
The University of Oklahoma Health Sciences Center
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
Wake Forest University Health Sciences
Imperial College London
Instituto de Parasitologia y Biomedicina López-Neyra, CSIC, Granada, Spain
Medical University of South Carolina
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-Senior Authors
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

Background:

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with varied and potentially severe clinical manifestations affecting multiple organs. Prevalence of this disease varies between genders and among age-groups and ethnicities. SLE affects women nine times greater than men and is more common in non-Caucasians than in Caucasians. Recent studies indicate that genetic variants in the region of tumor necrosis factor alpha-induced protein 3 (TNFAIP3) are associated with SLE in subjects of European and Asian ancestry. TNFAIP3 encodes a zinc-finger protein called A20, a critical regulator of inflammatory signaling pathways. To further characterize and localize the effect of TNFAIP3, we genotyped and imputed single-nucleotide polymorphisms (SNPs) within and flanking TNFAIP3 in multiple populations: European, African-American, Asian including Korean, Hispanic enriched for Amerindian-European admixture, and Gullah populations.

Methods:

Using a custom designed SNP panel for the Illumina iSelect system, we genotyped 127 SNPs in and around TNFAIP3 and 343 ancestry-informative markers (AIMs) in a total of 8922 SLE unrelated cases and 8077 controls. Then, using HapMap Phase III and 1000 Genomes Project data we imputed a minimum of 274 additional SNPs for each of the populations (the number varied based on linkage disequilibrium structure). 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, global and local ancestry adjustments under additive, dominant, and recessive models.

Results:

Association analysis identified risk haplotypes in Europeans and Asians likely to harbor a causal variant. Further haplotype comparisons across populations revealed a variant that likely explains the majority of the genetic association between SLE and TNFAIP3 identified in our study populations with P=1.96 × 10E-8, OR=1.69, 95% CI=1.41–2.04 in Europeans, P=3.30 × 10E-9, OR= 2.26, 95% CI=1.73–2.97 in Asians, and P=1.24 × 10E-9, OR=2.53, 95% CI=1.88–3.41 in Koreans alone. No significant association was found in other populations.

Conclusion:

These results support genetic association with SLE in the region of TNFAIP3, unique to Europeans and Asians and further demonstrate the complexity of identifying associations across different populations. Sequencing and functional studies are necessary to validate this variant and determine the contribution of TNFAIP3 to SLE.

To cite this abstract, please use the following information:
Adrianto, Indra, Lessard, Christopher J., Kaufman, Kenneth M., Anaya, Juan-Manuel, Networks, Marta E. Alarcón-Riquelme on Behalf of the BIOLUPUS and GENLES, Bae, Sang-Cheol, et al; Association of Variants in the TNFAIP3 Region with Systemic Lupus Erythematosus in a Multi-Ethnic Study. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1585
DOI: 10.1002/art.29351

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