Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
A Functional Haplotype in the Region of TNIP1 Is Associated with Systemic Lupus Erythematosus in Multiple Populations.
Adrianto1, Indra, Wiley1, Graham B., Wang1, Shaofeng, Kaufman2, Kenneth M., Anaya3, Juan-Manuel, Alarcon-Riquelme, Marta E., on behalf of BIOLUPUS and GENLES networks,
Oklahoma Medical Research Foundation, Oklahoma City, OK
Oklahoma Medical Research Foundation and Oklahoma University Health Sciences Center, Oklahoma City, OK
Instituto de Parasitologia y Biomedicina Lopez-Neyra (CSIC), Granada, Spain
University of Chicago, Chicago, IL
David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA
Divisions of Genetics and Molecular Medicine and Immunology, King's College London, London, United Kingdom
Cincinnati Children's Hospital Medical Center and the US Department of Veterans Affairs Medical Center, Cincinnati, OH
Univ of Texas SW Med Ctr, Dallas, TX
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation and US Department of Veterans Affairs Medical Center, Oklahoma City, OK
Universidad del Rosario-Corporacion para Investigaciones Biologicas, Bogota, Colombia
Hanyang University Hospital for Rheumatic Diseases, Clinical Research Center for Rheumatoid Arthritis (CRCRA), Seoul, South Korea
University of Alabama at Birmingham, Birmingham, AL
Wake Forest School of Medicine, Winston-Salem, NC
Division of Rheumatologyand Immunology, Medical University of South Carolina, Charleston, SC
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
Recent genome-wide association studies (GWAS) in Asian and European-ancestry (EA) populations have revealed genetic variants in the vicinity of TNIP1 to be associated with systemic lupus erythematosus (SLE), an autoimmune disease characterized by loss of tolerance to self-antigens and dysregulated interferon responses. TNIP1 encodes for the adapter protein ABIN1 that recruits A20 to polyubiquitinated NEMO (IKKg) facilitating NEMO deubiquitination and restriction of NF-kB signaling. To fully characterize the variants in TNIP1 responsible for association with SLE, we performed fine mapping, resequencing, and imputation using single-nucleotide polymorphisms (SNPs) within TNIP1 on chromosome 5q33 in five ethnically diverse populations.
Genotyping was performed on the Illumina iSelect platform for 83 SNPs within TNIP1 in the following cases and controls: African-American (AA) (1,569/1,893), Asian (1,328/1,348), EA (4,248/3,818), Gullah (155/131) and Hispanic (1,622/887) populations. Imputation was conducted using IMPUTE2 and the 1000 Genomes Project haplotypes. Imputation using targeted resequencing data from 187 EA and 46 AA individuals was also performed in order to improve ascertainment of causal alleles enriched in SLE patients. The single marker association analyses were performed using logistic regression in PLINK. Conditional analyses adjusting for each haplotype-tagging variant were done using logistic regression. Haplotypes were estimated followed by haplotypic association using Haploview. Western blotting was performed to compare the basal protein expression level of ABIN1 in the EBV-transformed B cell lines of 9 individuals with risk haplotypes and 7 individuals with non-risk haplotype.
The peak associations of variants within TNIP1 were observed in EA (P = 2.24 × 10-11), Hispanic (P = 8.00 × 10-7), and AA (P = 1.15 × 10-5) populations, respectively. We saw more modest association in Asians (P = 2.53 × 10-4), but no association in Gullah. In the EA population, we were able to dissect two independent risk haplotypes (H1 and H2) with P = 1.54 × 10-6 and P = 7.49 × 10-6 by conditional analyses. Interestingly, the H1 haplotype was also present in AAs and Hispanics, but we saw no evidence of the H2 haplotype in other populations. To determine if these risk haplotypes carry variants that influence the expression of ABIN1 protein, we used Western blotting in lysates from resting EBV transformed lymphocytes harboring either haplotype. We observed a significant decrease in ABIN1 protein expression (P = 0.0029) in 7 individuals with the H1 haplotype suggesting functional variants present on this haplotype influence susceptibility to autoimmunity by restricting ABIN1 expression.
We have comprehensively characterized the variants present within TNIP1 in five populations. In the EA population, we observed two risk haplotypes one of which was also seen in AAs and Hispanics. Variants present on this haplotype result in decreased ABIN1 protein expression. Further functional studies to investigate the role of TNIP1 in regulating autoimmunity are ongoing.
To cite this abstract, please use the following information:
Adrianto, Indra, Wiley, Graham B., Wang, Shaofeng, Kaufman, Kenneth M., Anaya, Juan-Manuel, Alarcon-Riquelme, Marta E., et al; A Functional Haplotype in the Region of TNIP1 Is Associated with Systemic Lupus Erythematosus in Multiple Populations. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :637