Interferon Regulatory Factor 5 Associates with Systemic Lupus Erythematosus Through Two Distinct and Independent Effects

Erin Zoller¹, Leah C. Kottyan², Bahram Namjou¹, Samuel Vaughn¹, Miranda C. Marion³, Carl D. Langefeld⁴, Marta E. Alarcon-Riquelme⁵, Juan-Manuel Anaya⁶, Elizabeth E. Brown on behalf of PROFILE⁷, Sang-Cheol Bae⁸, Jeffrey C. Edberg⁹, Patrick M. Gaffney¹⁰, Diane L. Kamen¹¹, Robert P. Kimberly¹², Chaim O. Jacob¹³, Joan T. Merrill¹⁴, Kathy Moser Sivils¹⁵, Michelle Petri¹⁶, Rosalind Ramsey-Goldman¹⁷, John D. Reveille¹⁸, Anne M. Stevens¹⁹, Betty P. Tsao²⁰, Luis M. Vila²¹, Timothy J. Vyse²² and Kenneth M. Kaufman²³, ¹Division of Rheumatology and The Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, ²Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, ³Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, NC, ⁴Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, ⁵Arthritis & Clinical Immunology, Oklahoma Medical Research Foundation, Center for Genomics and Oncological Research Pfizer-University of Granada-Junta de Andalucia, Oklahoma City, OK, ⁶School of Medicine and Health Sciences, Universidad del Rosario. Center for Autoimmune Diseases Research (CREA), Bogotá, Colombia, ⁷University of Alabama at Birmingham, Birmingham, AL, ⁸Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea, ⁹Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, ¹⁰Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ¹¹Department of Medicine, Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Charleston, SC, ¹²Clinical Immun & Rheumatology, University of Alabama at Birmingham, Birmingham, AL, ¹³Division of Rheumatology, University of Southern California Keck School of Medicine, Los Angeles, CA, ¹⁴Clinical Pharmacology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ¹⁵Oklahoma Medical Research Foundation, Oklahoma City, OK, ¹⁶Johns Hopkins University School of Medicine, Baltimore, MD, ¹⁷Medicine/Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL, ¹⁸Internal Medicine/Rheumatology, Univ of Texas Health Science Center at Houston, Houston, TX, ¹⁹Pediatrics, University of Washington, Seattle, WA, ²⁰Medicine/Rheumatology, UCLA School of Medicine, Los Angeles, CA, ²¹Department of Medicine, Division of Rheumatology, University of Puerto Rico Medical Sciences Campus, San Juan, PR, ²²Medical & Molecular Genetics, King's College London, London, United Kingdom, ²³1Center for Autoimmune Genomics and Etiology and Rheumatology Division, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati, Cincinnati, OH

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Systemic lupus erythematosus (SLE)

Session Information

Title: Systemic Lupus Erythematosus - Human Etiology and Pathogenesis I

Session Type: Abstract Submissions (ACR)

Background/Purpose: Powerful evidence suggests that Systemic lupus erythematous (SLE or lupus) autoimmunity is mediated by disregulation of the IRF5-NFκB signaling pathway. The interferon regulatory factor 5 (IRF5) genomic locus is associated with lupus and seven other autoimmune diseases in populations of each of the major ancestral groups. While the association of lupus with the IRF5 region has been extensively confirmed, previous publications have not presented a comprehensive analysis of the complete genetic variation of the entire locus including the juxtaposing gene TNPO3

Methods: In order to fine map the entire IRF5/TNPO3 region, we used an Illumina iSelect custom array to genotype 107 single nucleotide polymorphisms (SNPs) in 8,395 SLE cases and 7,367 controls of European, African American, Asian, Hispanic, and Native American ancestry. Additionally, we imputed genetic variants spanning the IRF5/TNP03 region and performed targeted deep sequencing of lupus cases and controls to identify over 7,000 variants in the region.

Results: Through direct genotyping, imputation, and deep sequencing, we have accounted for all variation within the IRF5/TNPO3 region and identified a set of variants that includes the causative polymorphism(s). In each ancestry group, we confirmed strong association of variants located in the promoter region of IRF5. Furthermore, in Europeans and populations with European admixture, we also observed a strong independent association that spans the IRF5 and TNPO3 genes marked by a large haplotype. Through step-wise conditional analysis of the variation, our model of association using these two independent effects is able to explain the entire association of the IRF5/TNPO3 region. Using an iterative strategy, we limited the list of possible causal polymorphisms to those present in the genetic models with the strongest lupus associations. We further demonstrated evidence for over-transmission of European-derived variants to African American cases by using global and local admixture analysis.

Conclusion: IRF5 association reflects a crucial component in the pathogenesis of lupus in multiple ancestral groups. With these studies, we present a model of association that is superior to other genetic models published to date: we show two distinct and independent effects within the IRF5/TNPO3 locus. Being convinced that we have identified all of the genetic variation relevant to the IRF5 association in the region of IRF5/TNPO3, we have therefore captured the causal variant(s). Identifying the independent genetic effects allows for the separate pursuit of causal polymorphisms within this defined variation and disease mechanisms yet to be described.

Disclosure:

E. Zoller,
None;

L. C. Kottyan,
None;

B. Namjou,
None;

S. Vaughn,
None;

M. C. Marion,
None;

C. D. Langefeld,
None;

M. E. Alarcon-Riquelme,
None;

J. M. Anaya,
None;

E. E. Brown on behalf of PROFILE,
None;

S. C. Bae,
None;

J. C. Edberg,
None;

P. M. Gaffney,
None;

D. L. Kamen,
None;

R. P. Kimberly,
None;

C. O. Jacob,
None;

J. T. Merrill,

HGS, GSK,

K. Moser Sivils,
None;

M. Petri,

HGS, GSK,

R. Ramsey-Goldman,
None;

J. D. Reveille,
None;

A. M. Stevens,
None;

B. P. Tsao,
None;

L. M. Vila,
None;

T. J. Vyse,
None;

K. M. Kaufman,
None.

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