ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1611

Targeted Deep Re-Sequencing Implicates Rare and Low Frequency Coding Variants in IL23R, MEFV, TLR4, and NOD2 in Behçet’s Disease

Yohei Kirino1, Qing Zhou1, Yoshiaki Ishigatsubo2, Nobuhisa Mizuki3, Ilknur Tugal-Tutkun4, Emire Seyahi5, Yilmaz Ozyazgan6, F. Sevgi Sacli7, Burak Erer8, Zeliha Emrence9, Atilla Cakar10, Duran Ustek10, Akira Meguro11, Atsuhisa Ueda2, Mitsuhiro Takeno2, Michael J. Ombrello1, Colleen Satorius12, Baishali Maskeri13, Jim Mullikin13, Hong-Wei Sun14, Gustavo Gutierrez-Cruz15, Yoonhee Kim16, Ahmet Gül17, Daniel L. Kastner12 and Elaine F. Remmers12, 1Inflammatory Disease Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 2Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan, 3Yokohama City University Graduate School of Medicine, Yokohama, Japan, 4Department of Ophthalmology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey, 5Rheumatology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey, 6Ophthalmology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey, 7Division of Rheumatology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey, 8Department of Internal Medicine, Rheumatology Division, Istanbul Faculty of Medicine, Istanbul University,, Istanbul, Turkey, 9Genetics, Institute for Experimental Medicine, Istanbul University, Istanbul, Turkey, 10Genetics, Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey, 11Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan, 12Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 13NIH intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Rockville, MD, 14Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 15Genome Analysis Core Facility, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 16Genometrics section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, 17Department of Internal Medicine, Division of Rheumatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

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 association studies (GWAS) have successfully identified common variants that contribute to Behçet’s disease (BD) susceptibility. However, associations due to rare and low-frequency variants have not been evaluated.  It has long been debated whether the innate immune system is involved in the pathogenesis of BD.  Clinical manifestations such as episodic inflammation and neutrophil recruitment to the sites of inflammation strongly suggest that the innate immune response plays an important role, although genetic evidence to support this hypothesis is sparse. Recent advances in sequencing technology allow investigators to re-sequence targeted genes to discover novel variants in large collections of cases with complex genetic traits and genetically matched controls.

Methods: We performed deep re-sequencing of two GWAS-identified genes (IL23R and IL10) and eleven genes known to have roles in innate immunity (IL1B, IL1R1, IL1RN, NLRP3, MEFV, TNFRSF1A, PSTPIP1, CASP1, PYCARD, NOD2, and TLR4) in 382 cases and 384 controls in Japanese population and 384 cases and 384 controls in Turkish population. Non-synonymous variants identified by deep exonic re-sequencing were validated by individual genotyping of 4955 samples. For statistical analyses, we performed C-alpha test, adaptive sum test and step-up methods to identify the roles of rare and low-frequency variants associated with BD.

Results: We found a non-random distribution of rare and low-frequency variants in cases and controls implicating IL23R, MEFV, TLR4, and NOD2 in BD susceptibility. Adaptive sum test and step-up methods corroborated the results for IL23R in both populations and for TLR4 in the Turkish population. Carriage of MEFV-M694V, known to cause recessively inherited familial Mediterranean fever, conferred BD risk in Turkish samples (Cochran-Mantel-Haenszel meta analysis p=1.79×10-12).

Conclusion: These findings implicate innate immune and bacterial sensing mechanisms in BD pathogenesis.  We are currently extending our re-sequencing efforts to CCR1, KLRK1, KLRC1-4, STAT4, and ERAP1, common variants of which we recently identified by GWAS.

Disclosure:

Y. Kirino,
None;

Q. Zhou,
None;

Y. Ishigatsubo,
None;

N. Mizuki,
None;

I. Tugal-Tutkun,
None;

E. Seyahi,
None;

Y. Ozyazgan,
None;

F. S. Sacli,
None;

B. Erer,
None;

Z. Emrence,
None;

A. Cakar,
None;

D. Ustek,
None;

A. Meguro,
None;

A. Ueda,
None;

M. Takeno,
None;

M. J. Ombrello,
None;

C. Satorius,
None;

B. Maskeri,
None;

J. Mullikin,
None;

H. W. Sun,
None;

G. Gutierrez-Cruz,
None;

Y. Kim,
None;

A. Gül,
None;

D. L. Kastner,

National Institutes of Health,

7;

E. F. Remmers,
None.

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