ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1703

High Density Genotyping Of Immune-Related Disease Genes Identifies 7 New Susceptibility Loci For Behçet’s Disease

Masaki Takeuchi1,2, Nobuhisa Mizuki2, Akira Meguro2, Michael J. Ombrello3, Colleen Satorius4, Yohei Kirino2, Tatsukata Kawagoe2, Duran Ustek5, Ilknur Tugal-tutkun6, Emire Seyahi7, Yilmaz Ozyazgan7, Shigeaki Ohno8, Atsuhisa Ueda2, Yoshiaki Ishigatsubo2, Ahmet Gül6,9, Daniel L. Kastner4 and Elaine Remmers4, 1Medical Genetics Branch, Inflammation Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 2Yokohama City University Graduate School of Medicine, Yokohama, Japan, 3Translational Genetics and Genomics Unit, National Institute of Arthritis Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 4Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 5Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey, 6Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey, 7Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey, 8Hokkaido University Graduate School of Medicine, Hokkaido, Japan, 9Department of Internal Medicine, Rheumatology Division, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: , ,

Session Information

Title: Genetics and Genomics of Rheumatic Disease I

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Genome-wide association studies have revealed susceptibility genes for many genetically complex diseases. The Immunochip is a custom array with 196,524 markers in 186 loci selected from analysis of 12 autoimmune diseases.  It enables dense genotyping of established immune disease-associated loci as well as genotyping of additional suggestive variants identified in immune diseases.  Behçet’s disease (BD) is a systemic vasculitis that manifests with oral ulcers, uveitis, skin inflammation, genital ulcers and inflammation in other organs.  Although HLA-B*51, IL10, IL23R, CCR1, STAT4, KLRC4, and ERAP1have been reported to be susceptibility genes in previous studies, the pathogenesis of BD remains unclear.  The purpose of this study was to perform dense genotyping of loci associated with immune diseases to identify novel susceptibility loci for BD.

Methods:

In this study, 2014 Turkish BD patients and 1826 controls were densely genotyped using the Immunochip.  Samples with call rate > 0.95 and markers with call rate > 0.95, minor allele frequency > 0.01, and Hardy-Weinberg equilibrium P value > 0.00001 were included.  Samples from related individuals with identity by descent pi-hat > 0.18 were excluded and principal components were used to evaluate population stratification.  For novel loci with association test P value < 5×10-6, additional SNPs in the region were imputed using 1000 Genomes data as the reference panel.  Imputed SNPs with info > 0.8 were included in the comprehensive association analysis.  P < 5×10-8 and P < 1.67×10-8were considered thresholds for genome-wide significance in the basic allele test analysis and the three model (additive, dominant, recessive) genotypic analysis, respectively.

Results:

The basic allele association test confirmed 2 loci, IL10 and CCR1, previously associated with BD and identified 4 novel loci, IL1A-IL1B, SCHIP1-IL12A, IRF8, and PTPN1, which exceeded genome-wide significance.  In addition, the FUT2 locus showed dominant model genome-wide significance in the three model genotypic analysis.  Imputation data provided 2 additional novel loci with genome-wide significance, RIPK2 and EGR2.

Conclusion:

This immunochip dense-genotyping study identified 7 new BD susceptibility loci. These results have greatly expanded the list of genes with common variants that influence BD susceptibility.  Some of these new loci implicate important pathways, such as the IL-1 pathway, which may help explain BD pathogenesis and suggest therapeutic targets.

 

Disclosure:

M. Takeuchi,
None;

N. Mizuki,
None;

A. Meguro,
None;

M. J. Ombrello,
None;

C. Satorius,
None;

Y. Kirino,
None;

T. Kawagoe,
None;

D. Ustek,
None;

I. Tugal-tutkun,
None;

E. Seyahi,
None;

Y. Ozyazgan,
None;

S. Ohno,
None;

A. Ueda,
None;

Y. Ishigatsubo,
None;

A. Gül,
None;

D. L. Kastner,
None;

E. Remmers,
None.

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