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 Large-Scale, Multi-Racial Replication Study Identifies Novel Systemic Lupus Erythematosus Susceptibility Loci At IRF8, TMEM39A, and IKZF3/ZPBP2.

Lessard1,  Christopher J., Adrianto1,  Indra, Ice1,  John A., Kelly1,  Jennifer A., Li1,  He, Wiley1,  Graham B., Rasmussen1,  Astrid

Oklahoma Medical Research Foundation, Oklahoma City, OK
Rosario, Argentina
UCLA School of Medicine, 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 and US Department of Veterans Affairs Medical Center, Oklahoma City, OK
Wake Forest University Health Sciences, Winston-Salem, NC
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK
Oklahoma Medical Research Foundation, Center for Genomics and Oncological Research Pfizer-University of Granada-Junta de Andalucia, 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
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
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

Background/Purpose:

Systemic lupus erythematosus (SLE) is a chronic, heterogeneous autoimmune disorder characterized by inflammation, loss of tolerance to self-antigens, and dysregulated interferon responses. In this study, we sought to replicate loci with suggestive association with SLE from a previously published genome-wide association scan.

Methods:

Genotyping was performed using Illumina iSelect technology. Stringent quality control measures were applied for Hardy- Weinberg proportions, missing genotypes, and excess missingness between cases and controls. In addition, genetic outliers were determined using principal component (PC) analysis. Only SNPs with minor allele frequencies >1% were considered. After quality control filtering, 3562 SLE cases and 3491 controls of European ancestry (EA), 1527 cases and 1811 controls of African-American (AA) descent, and 1265 cases and 1260 controls of Asian (AS) origin were included in the replication analysis. SNP-SLE association was tested using logistic regression under an additive genetic model in PLINK while adjusting for the first three PCs and gender. Meta-analysis was performed using METAL.

Results:

Three regions exceeded genome-wide significance (GWS) after the trans-racial replication study. One region that replicated in EA, AA, and AS subjects was located at 11q24.1 outside the 3'UTR region of interferon regulatory factor 8 (IRF8; Pmeta= 2.34 × 10E-9). Approximately 300 additional SNPs were genotyped in the region of IRF8. Two risk haplotypes were observed within the EA subjects (P= 3.85 × 10E-7 and P= 7.99 × 10E-10). Logistic regression conditioning on the most significant SNP in each haplotype indicated that these effects were independent. The other two loci included a coding SNP in TMEM39A (transmembrane protein 39A; Pmeta= 8.62 × 10E-9), and an intra-genic SNP at 17q21 between the genes IKZF3/ZBP2 in a shared promoter region (Pmeta= 3.48 × 10E-9). All three regions have been implicated in other autoimmune diseases. In addition, 13 other loci were replicated in EA but did not exceed GWS with 5 × 10E-8 < P < 9.99 × 10E-5 (CFHR1, CADM2, LOC730109/IL12a, LPP, LOC63920, SLU7, ADATMTSL1, C10orf64, SEN3, OR8D4, FAM19A2, STXBP6, and TMCO5).

Conclusion:

IRF8 is a transcription factor involved in the regulation of the interferon pathway, which has been widely reported to be dysregulated in SLE and other autoimmune diseases. No biologically relevant data has been published for TMEM39A. Association with IRF8 and TMEM39A has been previously reported with multiple sclerosis (MS). IKZF3 is an important transcription factor regulating B lymphocyte proliferation and differentiation. Multiple other autoimmune diseases have identified association with this interval, including Crohn's disease, ulcerative colitis, primary biliary cirrhosis, and rheumatoid arthritis. Thus, this study identified 3 novel SLE risk loci exceeding GWS and replicated 13 additional loci suggestive of association.

To cite this abstract, please use the following information:
Lessard, Christopher J., Adrianto, Indra, Ice, John A., Kelly, Jennifer A., Li, He, Wiley, Graham B., et al; A Large-Scale, Multi-Racial Replication Study Identifies Novel Systemic Lupus Erythematosus Susceptibility Loci At IRF8, TMEM39A, and IKZF3/ZPBP2. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2475
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