ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1614

Analysis of the Immunochip in a Large Cohort of Juvenile Idiopathic Arthritis Cases Identifies 17 Loci At Genome-Wide Significance

Anne Hinks1, Joanna Cobb1, Miranda C. Marion2, Marc Sudman3, John Bowes4, Kathryn J. A. Steel5, Mehdi Keddache6, John F. Bohnsack7, Stephen Guthery8, Lucy R. Wedderburn9, Johannes Peter Haas10, David N. Glass11, Sampath Prahalad12, Carl D. Langefeld13, Wendy Thomson5 and Susan D. Thompson3, 1Arthritis Research UK Epidemiology Unit, Manchester Academic Health Sciences Centre, Institute of Inflammation and Repair, The University of Manchester, Manchester, United Kingdom, 2Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, NC, 3Department of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 4Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester, United Kingdom, 5Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester, United Kingdom, 6Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 7Pediatriacs, University of Utah, Salt Lake City, UT, 8Pediatrics, University of Utah, Salt Lake City, UT, 9Rheumatology Unit , Institute of Child Health, University College London (UCL), London, United Kingdom, 10German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany, 11Divison of Rheumatology, Cincinnati Childrens Hospital Medical Center, Cincinnati, OH, 12Pediatrics, Emory Children's Center, Atlanta, GA, 13Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords:

Session Information

Title: Genetics and Genomics of Rheumatic Diseases

Session Type: Abstract Submissions (ACR)

Background/Purpose: Genome-wide (GW) association studies have been hugely successful in the identification of susceptibility loci for autoimmune diseases, interestingly many of the loci are shared across these diseases. The regions identified now require more detailed fine-mapping to localize the association signal and identify putative functional variants. The Immunochip consortium was established to pool ~180 loci from 12 diseases to include on a custom genotyping chip. Juvenile idiopathic arthritis (JIA) is the most common arthritic disease of childhood. Candidate gene studies have identified a number of common autoimmune genes that confer susceptibility to JIA. However, JIA has been less well studied using large-scale approaches. This study aimed to perform genotyping on the Immunochip to allow fine-mapping of previously associated regions and to identifying novel loci for JIA.

Methods: Genotyping was performed using the Immunochip in a large cohort from the UK, US and Germany comprising a total of 2816 JIA oligoarthritis and RF- polyarthritis cases and 13056 controls. Standard SNP and sample QC was performed, including removing samples with call rate <98%, outliers of mean heterozygosity and ancestral outliers. Each SNP was assessed for departure from an additive genetic model, and analyzed under the most appropriate model (either additive, dominant or recessive) using SNPGWA vers4.0 and adjusting for the top 5 principal components. Within regions reaching the GW significance threshold (P<5x10-8), conditional logistic regression was used to test for independent effects.

Results: This analysis has confirmed loci previously associated with JIA at P<5x10-8 (HLA, PTPN22, PTPN2), has strengthened the association of other previously investigated regions (STAT4, IL2/IL21, IL2RA, SH2B3) and has identified novel regions (ANKRD55, TYK2, IRF1, UBE2L3, LNPEP, IL2RB, RUNX1, IL6R, ZFP36L1/RAD51B, FAS) such that all 17 now reach GW significance. The STAT4, PTPN2, IL2RA regions show evidence for multiple independent effects, some of which are low-frequency variants. A further 9 novel loci have been identified at a suggestive level of significance (P<1x10-6). Some showed weak evidence previously (COG6, CCR5) and others have not been associated with JIA to date (RUNX3, LTBR, PRM1). The dense-mapping of some loci on the Immunochip along with bioinformatic analysis has refined the association to a single gene for 7 regions.

Conclusion:

The Immunochip project enables cost-effective fine-mapping of autoimmune loci in diseases such as JIA. This analysis has confirmed and strengthened the association of previously associated genes as well as identified novel susceptibility loci for JIA. It highlights several crucial pathways, such as the IL2 pathway in JIA disease pathogenesis. Analysis of the Immunochip in this dataset, the largest cohort of JIA cases investigated to date, has greatly increased our knowledge of the genetic basis of susceptibility for JIA.

Acknowledgements: Childhood Arthritis Prospective Study, Childhood Arthritis Response to Medication Study, BSPAR study group, Cincinnati Registry for Juvenile Arthritis Genetics, Consortium for Juvenile Arthritis Genetics, USA-Juvenile Arthritis Genetics Cohort.

Disclosure:

A. Hinks,
None;

J. Cobb,
None;

M. C. Marion,
None;

M. Sudman,
None;

J. Bowes,
None;

K. J. A. Steel,
None;

M. Keddache,
None;

J. F. Bohnsack,
None;

S. Guthery,
None;

L. R. Wedderburn,
None;

J. P. Haas,
None;

D. N. Glass,
None;

S. Prahalad,
None;

C. D. Langefeld,
None;

W. Thomson,
None;

S. D. Thompson,
None.

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