Sarcoidosis is a genetically complex systemic inflammatory disease that affects multiple organs. We present a GWAS of a Japanese cohort (700 sarcoidosis cases and 886 controls) with replication in independent samples from Japan (931 cases and 1,042 controls) and the Czech Republic (265 cases and 264 controls). We identified three loci outside the HLA complex, CCL24, STYXL1-SRRM3, and C1orf141-IL23R, which showed genome-wide significant associations (P < 5.0 × 10-8) with sarcoidosis; CCL24 and STYXL1-SRRM3 were novel. The disease-risk alleles in CCL24 and IL23R were associated with reduced CCL24 and IL23R expression, respectively. The disease-risk allele in STYXL1-SRRM3 was associated with elevated POR expression. These results suggest that genetic control of CCL24, POR, and IL23R expression contribute to the pathogenesis of sarcoidosis. We speculate that the CCL24 risk allele might be involved in a polarized Th1 response in sarcoidosis, and that POR and IL23R risk alleles may lead to diminished host defense against sarcoidosis pathogens.

2nd Division Department of Internal Medicine Hamamatsu University School of Medicine 1 20 1 Handayama Hamamatsu Shizuoka 431 3192 Japan

Department of Immunology Faculty of Medicine and Dentistry Palacky University 1 P Pavlova Str 6 77520 Olomouc Czech Republic

Department of Internal Medicine National Hospital Organization Nishibeppu National Hospital 4548 Oaza Tsurumi Beppu Oita 874 0840 Japan

Department of Medical Biochemistry Kurume University School of Medicine 67 Asahimachi Kurume Fukuoka 830 0011 Japan

Department of Medical Science and Cardiorenal Medicine Yokohama City University School of Medicine 3 9 Fukuura Kanazawa ku Yokohama Kanagawa 236 0004 Japan

Department of Molecular Life Science Division of Molecular Medical Science and Molecular Medicine Tokai University School of Medicine 143 Shimokasuya Isehara Kanagawa 259 1193 Japan

Department of Ophthalmology and Visual Science Tokyo Medical and Dental University Graduate School of Medicine 1 5 45 Yushima Bunkyo ku Tokyo 113 8519 Japan

Department of Ophthalmology and Visual Science Yokohama City University Graduate School of Medicine 3 9 Fukuura Kanazawa ku Yokohama Kanagawa 236 0004 Japan

Department of Ophthalmology Faculty of Medicine and Graduate School of Medicine Hokkaido University N15 W7 Kita ku Sapporo Hokkaido 060 8638 Japan

Department of Ophthalmology Health Sciences University of Hokkaido Ainosato 2 5 Kita ku Sapporo Hokkaido 002 8072 Japan

Department of Ophthalmology Japan Community Health care Organization Osaka Hospital 4 2 78 Fukushima Fukushima ku Osaka 553 0003 Japan

Department of Ophthalmology Keio University School of Medicine 35 Shinanomachi Shinjuku ku Tokyo 160 0016 Japan

Department of Ophthalmology Kitasato Institute Hospital 5 9 1 Shirokane Minato ku Tokyo 108 8642 Japan

Department of Ophthalmology Kono Medical Clinic 3 30 28 Soshigaya Setagaya ku Tokyo 157 0072 Japan

Department of Ophthalmology National Defense Medical College 3 2 Namiki Tokorozawa Saitama 359 8513 Japan

Department of Ophthalmology Nippon Medical School 1 1 5 Sendagi Bunkyo ku Tokyo 113 8602 Japan

Department of Ophthalmology School of Medicine Sapporo Medical University S1 W16 Chuo ku Sapporo Hokkaido 060 8543 Japan

Department of Ophthalmology Tokyo Medical University 6 7 1 Nishishinjuku Shinjuku ku Tokyo 160 0023 Japan

Department of Ophthalmology University of Tokyo School of Medicine 7 3 1 Hongo Bunkyo ku Tokyo 113 8655 Japan

Department of Pathological Physiology Faculty of Medicine and Dentistry Palacky University Hnevotinska Str 77515 Olomouc Czech Republic

Department of Pulmonology Yokohama City University Graduate School of Medicine 3 9 Fukuura Kanazawa ku Yokohama Kanagawa 236 0004 Japan

Department of Respiratory Diseases Kumamoto City Hospital 1 1 60 Kotoh Kumamoto Kumamoto 862 8505 Japan

Department of Respiratory Medicine Faculty of Medicine and Dentistry Palacky University 1 P Pavlova Str 6 77900 Olomouc Czech Republic

Department of Respiratory Medicine Japan Railway Sapporo Hospital Higashi 1 Kita 3 Chuo ku Sapporo 060 0033 Japan

Department of Respiratory Medicine Japan Railway Tokyo General Hospital 2 1 3 Yoyogi Shibuya ku Tokyo 151 0053 Japan

Department of Respiratory Medicine Japanese Red Cross Medical Centre 4 1 22 Hiroo Shibuya ku Tokyo 150 8953 Japan

Division of Cardiology Department of Internal Medicine Fujita Health University School of Medicine 1 98 Dengakugakubo Kutsukakecho Toyoake Aichi 470 1192 Japan

Division of Genome Analysis Institute of Bioregulation Kyushu University 3 1 1 Maidashi Higashi ku Fukuoka Fukuoka 812 8582 Japan

Division of Hepatology and Gastroenterology Department of Medicine Shinshu University School of Medicine 3 1 1 Asahi Matsumoto Nagano 390 8621 Japan

Division of Pulmonary Medicine Department of Medicine Jichi Medical University 3311 1 Yakushiji Shimotsuke Tochigi 329 0498 Japan

Division of Respiratory Medicine and Allergology Aichi Medical University 21 Karimata Yazako Nagakute cho Aichi gun Aichi 480 1195 Japan

Inflammatory Disease Section National Human Genome Research Institute National Institutes of Health 10 Center Drive 10 CRC East B2 5235 Bethesda MD 20892 1849 USA

INSERM Franco Japanese Laboratoire International Associé Nextgen HLA Laboratory Nagano Japan

INSERM Franco Japanese Laboratoire International Associé Nextgen HLA Laboratory Strasbourg France

Kyoto Central Clinic Clinical Research Center 56 58 Masuyacho Sanjo Takakura Nakagyo ku Kyoto 604 8111 Japan

Plateforme GENOMAX Laboratoire d'ImmunoRhumatologie Moléculaire INSERM UMR_S1109 LabEx Transplantex Centre de Recherche d'Immunologie et d'Hématologie Faculté de Médecine Fédération Hospitalo Universitaire Université de Strasbourg Strasbourg France

Yuasa Eye Clinic 3 1 1 Nishimoto cho Nishi ku Osaka 550 0005 Japan

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