Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.

Homozygous 3.2kb Deletion in LEPREL1 (P3H2) Intron 1 Reduces Cytokine Production and Protects from Multiple Inflammatory Diseases.

Kirino14,  Yohei, Ombrello15,  Michael J., Gul11,  Ahmet, Wang1,  Kai, Meguro7,  Akira, Yang14,  Barbara, Gadina14,  Massimo

Center for Applied Genomics, The Children's Hospital of Philadelphia
Graduate School of Medical Science and Engineering, KAIST
Istanbul Faculty of Medicine, Department of Internal Medicine, Division of Rheumatology, Istanbul University
N Shore Univ Hosp Rsch Ctr, Manhasset, NY
NIAMS, NIH, Bethesda, MD
NIAMS/National Institute of Health
NIAMS/National Institute of Health, Bethesda, MD
University of Texas M. D. Anderson Cancer Center
Yokohama City Grad Sch of Med, Yokohama, Japan
Department of Dermatology, Yonsei University College of Medicine
Department of Genetics, Institute for Experimental Medicine
Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine
Department of Molecular Life Science, Division of Molecular Medical Science and Molecular Medicine, Tokai University School of Medicine
Department of Ocular Inflammation and Immunology, Hokkaido University Graduate School of Medicine
Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine
Department of Rheumatology, Athens Medical Center, Athens, Greece
Departments of Medicine, Immunology and Molecular Genetics, Department of Medicine, University of Toronto, Mount Sinai Hospital and University Health Network

SNP genome-wide association studies (GWAS) are a powerful means to detect disease-associated variants, though it is difficult to detect rare or structural variants. Accumulating evidence has shown an involvement of gene copy number variation (CNV) in inflammatory diseases including systemic lupus erythematosus and psoriasis, suggesting that CNV analysis may be a promising means to identify novel disease-associated loci in rheumatic diseases. SNP marker intensity data from our previous Turkish Behcet's disease (BD) GWAS (1215 cases and 1278 controls) revealed a common 3.2kb deletion in LEPREL1 intron1 (odds ratio (OR)=0.62, p=6.5×10-4), homozygous deletions of which appeared to protect individuals from disease development. This association of homozygous LEPREL1 deletion replicated in a Japanese BD collection (382 cases and 410 controls, OR=0.64, p=0.014). Independent BD collections showed trend toward protection from the disease (combined cases n=1821, controls n=2005, OR=0.63, meta analaysis p=2.9×10-6). As the homozygous deletion in LEPREL1 was found to be common in both Turkish and Japanese populations, we sought to determine whether the deletion influences other inflammatory diseases, or in other ethnicities, as well. We found that patients with rheumatoid arthritis (combined cases n=1351, controls n=1659, OR=0.76, p=0.019), and type 1 diabetes (cases n=2214, controls n=2645, OR=0.82, p=0.038) were also protected from the disease, and trend towards protection in juvenile-onset Crohn's disease and primary biliary cirrhosis was observed. A meta-analysis of these combined inflammatory diseases (cases n=6406, controls n=6309) supports our hypothesis that LEPREL1 has a role in inflammation (p=2.4×10-7).

LEPREL1, a prolyl 3-hydroxylase which is also called P3H2, is involved in type IV collagen modification. This gene appears to have additional functions. Although the protein is expressed in lymph nodes, there has been no direct evidence linking LEPREL1 to inflammation. We found that LEPREL1 is primarily expressed in dendritic cells, and peripheral lymphocytes from individuals homozygous for this deleted region produce less LEPREL1 and inflammatory cytokines following exposure to stimulators of innate immunity. Our results offer new insights into the role an intragenic copy number variation plays in repressing development of inflammatory disease and reveal a novel modulatory mechanism for inflammation.

To cite this abstract, please use the following information:
Kirino, Yohei, Ombrello, Michael J., Gul, Ahmet, Wang, Kai, Meguro, Akira, Yang, Barbara, et al; Homozygous 3.2kb Deletion in LEPREL1 (P3H2) Intron 1 Reduces Cytokine Production and Protects from Multiple Inflammatory Diseases. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2217
DOI: 10.1002/art.29981

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