Identification of susceptibility genes for HLA-associated diseases including Behcet's disease

• Project Area: HLA polymorphism, disease and evolution
• Project/Area Number: 22133010
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Yokohama City University
• Principal Investigator: MIZUKI Nobuhisa 横浜市立大学, 医学(系)研究科(研究院), 教授 (90336579)
• Co-Investigator(Kenkyū-buntansha): KAWAGOE Tatsukata 横浜市立大学, 医学部, 助教 (20564800) ; OHNO Shigeaki 北海道大学, 医学研究科, 名誉教授 (50002382)
• Research Collaborator: MEGURO Akira ; TAKEUCHI Masaki ; REMMERS Elaine F.
• Project Period (FY): 2010-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥59,410,000 (Direct Cost: ¥45,700,000、Indirect Cost: ¥13,710,000); Fiscal Year 2014: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000); Fiscal Year 2013: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000); Fiscal Year 2012: ¥11,310,000 (Direct Cost: ¥8,700,000、Indirect Cost: ¥2,610,000); Fiscal Year 2011: ¥11,180,000 (Direct Cost: ¥8,600,000、Indirect Cost: ¥2,580,000); Fiscal Year 2010: ¥11,440,000 (Direct Cost: ¥8,800,000、Indirect Cost: ¥2,640,000)
• Keywords: HLA関連遺伝性眼疾患 / ベーチェット病 / サルコイドーシス / 原田病 / 原田

Outline of Final Research Achievements

The endoplasmic reticulum aminopeptidase 1 (ERAP1) is centrally involved in peptide trimming before HLA class I presentation. This study found that ERAP1 polymorphisms are associated with Behcet's disease and that also identified evidence of a gene-gene interaction between HLA-B*51 and ERAP1 in the disease.
This study showed associations between certain HLA-DRB1/HLA-DQB1 alleles and sarcoidosis in a Japanese population. In addition, We found an association between BTNL2, located in close proximity to HLA-DRB1 and HLA-DQB1, and also clarified whether the BTNL2 association is independent of the HLA risk alleles.

Research Products

• [Journal Article] Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia. (2015)
  • Author(s): Miyake M, Yamashiro K, Tabara Y, Suda K, Morooka S, Nakanishi H, Khor CC, Chen P, Qiao F, Nakata I, Akagi-Kurashige Y, Gotoh N, Tsujikawa A, Meguro A, Kusuhara S, Polasek O, Hayward C, Wright AF, Campbell H, Mizuki N, et al
  • Journal Title: Nat Commun Volume: 印刷中 Issue: 1 Pages: 6689-6689
  • DOI: 10.1038/ncomms7689
  • Peer Reviewed / Open Access
• [Journal Article] Semaphorin 3A controls allergic and inflammatory responses in experimental allergic conjunctivitis. (2015)
  • Author(s): Tanaka J, Tanaka H, Mizuki N, Nomura E, Ito N, Nomura N, Yamane M, Hida T, Goshima Y, Hatano H, Nakagawa H
  • Journal Title: Int J Ophthalmol Volume: 8(1) Pages: 1-10
  • Peer Reviewed / Open Access
• [Journal Article] Development and validation of new diagnostic criteria for acute retinal necrosis. (2015)
  • Author(s): Takase H, Okada AA, Goto H, Mizuki N, Namba K, Ohguro N, Sonoda KH, Tomita M, Keino H, Kezuka T, Kubono R, Mizuuchi K, Shibuya E, Takahashi H, Yanai R, Mochizuki M
  • Journal Title: Jpn J Ophthalmol Volume: 59(1) Issue: 1 Pages: 14-20
  • DOI: 10.1007/s10384-014-0362-0
  • NAID: 210000165197
  • Peer Reviewed / Open Access
• [Journal Article] Identification of possible pathogenic pathways in Behçet's disease using genome-wide association study data from two different populations. (2015)
  • Author(s): Bakir-Gungor B, Remmers EF, Meguro A, Mizuki N, Kastner DL, Gul A, Sezerman OU
  • Journal Title: Eur J Hum Genet Volume: 23(5) Issue: 5 Pages: 678-687
  • DOI: 10.1038/ejhg.2014.158
  • Peer Reviewed
• [Journal Article] Evaluation of the long-term efficacy and safety of infliximab treatment for uveitis in Behçet's disease: a multicenter study. (2014)
  • Author(s): Takeuchi M, Kezuka T, Sugita S, Keino H, Namba K, Kaburaki T, Maruyama K, Nakai K, Hijioka K, Shibuya E, Komae K, Hori J, Ohguro N, Sonoda KH, Mizuki N, Okada AA, Ishibashi T, Goto H, Mochizuki M
  • Journal Title: Ophthalmology Volume: 121(10) Issue: 10 Pages: 1877-1884
  • DOI: 10.1016/j.ophtha.2014.04.042
  • Peer Reviewed / Open Access
• [Journal Article] Trabeculotomy ab interno with internal limiting membrane forceps for open-angle glaucoma. (2014)
  • Author(s): Nakasato H, Uemoto R, Isozaki M, Meguro A, Kawagoe T, Mizuki N
  • Journal Title: Graefes Arch Clin Exp Ophthalmol Volume: 252(6) Issue: 6 Pages: 977-982
  • DOI: 10.1007/s00417-014-2616-4
  • Peer Reviewed
• [Journal Article] Treatment of symptomatic inferior conjunctivochalasis by ligation. (2014)
  • Author(s): Nakasato H, Uemoto R, Meguro A, Kawagoe T, Hatano H, Mizuki N
  • Journal Title: Acta Ophthalmol Volume: 印刷中 Issue: 5
  • DOI: 10.1111/aos.12349
  • Peer Reviewed
• [Journal Article] Behçet's disease ocular attack score 24: evaluation of ocular disease activity before and after initiation of infliximab. (2014)
  • Author(s): Kaburaki T, Namba K, Sonoda KH, Kezuka T, Keino H, Fukuhara T, Kamoi K, Nakai K, Mizuki N, Ohguro N; Ocular Behçet Disease Research Group of Japan
  • Journal Title: Jpn J Ophthalmol Volume: 58(2) Issue: 2 Pages: 120-130
  • DOI: 10.1007/s10384-013-0294-0
  • NAID: 40020019721
  • Peer Reviewed / Open Access
• [Journal Article] Association study of fibroblast growth factor 10 (FGF10) polymorphisms with susceptibility to extreme myopia in a Japanese population. (2013)
  • Author(s): Yoshida M, Meguro A, Okada E, Nomura N, Mizuki N
  • Journal Title: Mol Vis Volume: 19 Pages: 2321-2329
  • Peer Reviewed
• [Journal Article] Association study of IGF1 polymorphisms with susceptibility to high myopia in a Japanese population. (2013)
  • Author(s): Yoshida M, Meguro A, Yoshino A, Nomura N, Okada E, Mizuki N
  • Journal Title: Clin Ophthalmol Volume: 7 Pages: 2057-2062
  • DOI: 10.2147/opth.s52726
  • Peer Reviewed
• [Journal Article] Cataract surgery for tilted lens in peters' anomaly type 2. (2013)
  • Author(s): Nishide T, Nakanishi M, Hayakawa N, Kimura I, Mizuki N
  • Journal Title: Case Rep Ophthalmol Volume: 4(3) Issue: 3 Pages: 134-137
  • DOI: 10.1159/000354611
  • Peer Reviewed
• [Journal Article] Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error. (2013)
  • Author(s): Cheng CY, Schache M, Ikram MK, Young TL, Guggenheim JA, Vitart V, MacGregor S, Verhoeven VJ, Barathi VA, Liao J, Hysi PG, Bailey-Wilson JE, St Pourcain B, Kemp JP, McMahon G, Timpson NJ, Evans DM, Montgomery GW, Meguro A, Mizuki N, et al
  • Journal Title: Am J Hum Genet Volume: 93(2) Issue: 2 Pages: 264-277
  • DOI: 10.1016/j.ajhg.2013.06.016
  • Peer Reviewed
• [Journal Article] Comparison of LogMAR Eye charts with angular vision for visually impaired: the Berkeley rudimentary vision test vs LogMAR One target Landolt ring Eye chart. (2013)
  • Author(s): Miwa M, Iwanami M, Oba MS, Mizuki N, Nishida T
  • Journal Title: Graefes Arch Clin Exp Ophthalmol Volume: 251(12) Issue: 12 Pages: 2761-2767
  • DOI: 10.1007/s00417-013-2469-2
  • Peer Reviewed
• [Journal Article] Dogs and humans share a common susceptibility gene SRBD1 for glaucoma risk. (2013)
  • Author(s): Kanemaki N, Tchedre KT, Imayasu M, Kawarai S, Sakaguchi M, Yoshino A, Itoh N, Meguro A, Mizuki N
  • Journal Title: PLoS One Volume: 8(9) Issue: 9 Pages: e74372-e74372
  • DOI: 10.1371/journal.pone.0074372
  • Peer Reviewed
• [Journal Article] Reduction in choroidal thickness of macular area in polypoidal choroidal vasculopathy patients after intravitreal ranibizumab therapy. (2013)
  • Author(s): Nishide T, Hayakawa N, Nakanishi M, Ishii M, Okazaki S, Kimura I, Shibuya E, Mizuki N
  • Journal Title: Graefes Arch Clin Exp Ophthalmol Volume: 251(10) Issue: 10 Pages: 2415-2420
  • DOI: 10.1007/s00417-013-2419-z
  • Peer Reviewed
• [Journal Article] Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease. (2013)
  • Author(s): Kirino Y, Zhou Q, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E, Özyazgan Y, Ugurlu S, Erer B, Abaci N, Ustek D, Meguro A, Ueda A, Takeno M, Inoko H, Ombrello MJ, Satorius CL, Maskeri B, Mullikin JC, Sun HW, et al
  • Journal Title: Proc Natl Acad Sci U S A Volume: 110(20) Issue: 20 Pages: 8134-8139
  • DOI: 10.1073/pnas.1306352110
  • Peer Reviewed
• [Journal Article] Investigation of the association between Toll-like receptor 9 gene polymorphisms and sarcoidosis in Japanese patients. (2013)
  • Author(s): Yotsumoto S, Meguro A, Ishihara M, Uemoto R, Ota M, Morimoto S, Kaburaki T, Ando Y, Takenaka S, Ohno S, Inoko H, Mizuki N
  • Journal Title: Ocul Immunol Inflamm Volume: 21(3) Issue: 3 Pages: 234-236
  • DOI: 10.3109/09273948.2012.756114
  • Peer Reviewed
• [Journal Article] Interleukin 1 beta promoter polymorphism is associated with keratoconus in a Japanese population. (2013)
  • Author(s): Mikami T, Meguro A, Teshigawara T, Takeuchi M, Uemoto R, Kawagoe T, Nomura E, Asukata Y, Ishioka M, Iwasaki M, Fukagawa K, Konomi K, Shimazaki J, Nishida T, Mizuki N
  • Journal Title: Mol Vis Volume: 19 Pages: 845-851
  • Peer Reviewed
• [Journal Article] Preoperative factors associated with improvement in visual acuity after globe rupture treatment. (2013)
  • Author(s): Nishide T, Hayakawa N, Nakanishi M, Ishii M, Kimura I, Shibuya E, Nomura E, Mizuki N
  • Journal Title: Eur J Ophthalmol Volume: 23(5) Issue: 5 Pages: 718-722
  • DOI: 10.5301/ejo.5000252
  • Peer Reviewed
• [Journal Article] Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behcet disease. (2013)
  • Author(s): Kirino Y
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Investigation of the Association Between Toll-like Receptor 9 Gene Polymorphisms and Sarcoidosis in Japanese Patients. (2013)
  • Author(s): Yotsumoto S
  • Journal Title: Ocular Immunology and Inflammation Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Interleukin 1 beta promoter polymorphism is associated with keratoconus in a Japanese population. (2013)
  • Author(s): Mikami T
  • Journal Title: Molecular Vision Volume: 19 Pages: 845-851
  • Peer Reviewed
• [Journal Article] Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behcet's disease. (2013)
  • Author(s): Lee YJ
  • Journal Title: Annals of the Rheumatic Diseases Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Genome-wide association analysis identifies new susceptibility loci for Behcet's disease and epistasis between HLA-B*51 and ERAP1 (2012)
  • Author(s): Mizuki N, Meguro A
  • Journal Title: Nat Genet Volume: 45 Issue: 2 Pages: 202-7
  • DOI: 10.1038/ng.2520
  • Peer Reviewed
• [Journal Article] Genetic characterization and susceptibility for sarcoidosis in Japanese patients: risk factors of BTNL2 gene polymorphisms and HLA class II alleles (2012)
  • Author(s): Ota M, Meguro A, Kawagoe T, Mizuki N
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 53 Issue: 11 Pages: 7109-15
  • DOI: 10.1167/iovs.12-10491
  • Peer Reviewed
• [Journal Article] Common variants in the COL4A4 gene confer susceptibility to lattice degeneration of the retina (2012)
  • Author(s): Meguro A, Ota M, Kawagoe T, Mizuki N
  • Journal Title: PLoS One Volume: 7 Issue: 6 Pages: e39300-e39300
  • DOI: 10.1371/journal.pone.0039300
  • Peer Reviewed
• [Journal Article] Genetic variants on chromosome 1q41 influence ocular axial length and high myopia (2012)
  • Author(s): Meguro A, Mizuki N
  • Journal Title: PLoS Genet Volume: 8 Issue: 6 Pages: e1002753-e1002753
  • DOI: 10.1371/journal.pgen.1002753
  • Peer Reviewed
• [Journal Article] Lack of association between IL10 polymorphisms and sarcoidosis in Japanese patients. (2012)
  • Author(s): Sakuyama K
  • Journal Title: Molecular Vision Volume: 18 Pages: 512-518
  • Peer Reviewed
• [Journal Article] Confirmation of TBK1 duplication in normal tension glaucoma (2012)
  • Author(s): Kawase K, et al
  • Journal Title: Experimental Eye Research Volume: 96 Issue: 1 Pages: 178-180
  • DOI: 10.1016/j.exer.2011.12.021
  • Peer Reviewed
• [Journal Article] Factors associated with enlargement of chorioretinal atrophy after intravitreal bevacizumab for myopic choroidal neovascularization (2012)
  • Author(s): Uemoto R, et al
  • Journal Title: Graefe's Archive for Clinical and Experimental Ophthalmology Volume: (印刷中) Issue: 7 Pages: 989-97
  • DOI: 10.1007/s00417-011-1921-4
  • Peer Reviewed
• [Journal Article] Replication of a microsatellite genome-wide association study of Behcet's disease in a Korean population (2012)
  • Author(s): Horie Y, et al
  • Journal Title: Rheumatology Volume: (印刷中) Issue: 6 Pages: 983-6
  • DOI: 10.1093/rheumatology/ker444
  • Peer Reviewed
• [Journal Article] Lack of association between IL10 polymorphisms and sarcoidosis in Japanese patients (2012)
  • Author(s): Sakuyama K, et al
  • Journal Title: Molecular Vision Volume: 18 Pages: 512-518
  • Peer Reviewed
• [Journal Article] Anatomical and functional changes of retina following subretinal injection of high-speed fluid (2012)
  • Author(s): Uemoto R, et al
  • Journal Title: Graefe's Archive for Clinical and Experimental Ophthalmology Volume: 250 Issue: 3 Pages: 447-450
  • DOI: 10.1007/s00417-011-1800-z
  • Peer Reviewed
• [Journal Article] Investigation of Association between TLR9 Gene Polymorphisms and VKH in Japanese Patients (2011)
  • Author(s): Ito Ryuta; Ota Masao; Meguro Akira, et al
  • Journal Title: OCULAR IMMUNOLOGY AND INFLAMMATION Volume: 19:3 Issue: 3 Pages: 202-205
  • DOI: 10.3109/09273948.2011.553981
  • Peer Reviewed
• [Journal Article] Investigation of the association between SLC1A3 gene polymorphisms and normal tension glaucoma (2011)
  • Author(s): Yasumura R, et al
  • Journal Title: Molecular Vision Volume: 17 Pages: 792-736
  • Peer Reviewed
• [Journal Article] Toll-like receptor 2 (TLR2) gene polymorphisms are not associated with sarcoidosis in the Japanese (2011)
  • Author(s): Sato M, et al
  • Journal Title: Molecular Vision Volume: 17 Pages: 731-736
  • Peer Reviewed
• [Journal Article] Association analysis of Toll-like receptor 7 gene polymorphisms and Behcet's disease in Japanese (2011)
  • Author(s): Sada T, et al
  • Journal Title: Human Immunology Volume: 72 Issue: 3 Pages: 269-272
  • DOI: 10.1016/j.humimm.2010.12.007
  • Peer Reviewed
• [Journal Article] Investigation of the association between SLC1A3 gene polymorphisms and normal tension glaucoma. (2011)
  • Author(s): Yasumura R, et al
  • Journal Title: Mol Vis Volume: 17 Pages: 792-796
  • Peer Reviewed
• [Journal Article] Toll-like receptor 2 (TLR2) gene polymorphisms are not associated with sarcoidosis in the Japanese. (2011)
  • Author(s): Sato M, et al
  • Journal Title: Mol Vis Volume: 17 Pages: 731-736
  • Peer Reviewed
• [Journal Article] Association analysis of Toll-like receptor 7 gene polymorphisms and Behcet's disease in Japanese. (2011)
  • Author(s): Sada T, et al
  • Journal Title: Hum Immunol Volume: 72 Pages: 269-272
  • Peer Reviewed
• [Journal Article] Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behcet's disease susceptibility loci. (2010)
  • Author(s): Mizuki N, et al
  • Journal Title: Nat Genet Volume: 42 Pages: 703-706
  • Peer Reviewed
• [Journal Article] Genetics of Behcet disease inside and outside the MHC. (2010)
  • Author(s): Meguro A, et al
  • Journal Title: Ann Rheum Dis Volume: 69 Pages: 747-754
  • Peer Reviewed
• [Journal Article] Genome-wide association study of normal tension glaucoma : commonvariants in SRBD1 and ELOVL5 contribute to disease susceptibility (2010)
  • Author(s): Writing Committee for the Normal Tension Glaucoma Genetic Study Group of Japan Glaucoma Society
  • Journal Title: Ophthalmology Volume: 117 Pages: 1331-1338
  • Peer Reviewed
• [Journal Article] Genotyping HLA-DRB1 and HLA-DQB1 alleles in Japanese patients with normal tension glaucoma. (2010)
  • Author(s): Suzuki M, et al
  • Journal Title: Mol Vis Volume: 16 Pages: 1874-1879
  • Peer Reviewed
• [Journal Article] RIM39 and RNF39 are associated with Behcet's disease independently of HLA-B*51 and -A*26. (2010)
  • Author(s): Kurata R, et al
  • Journal Title: Biochem Biophys Res Commun Volume: 401 Pages: 533-537
  • Peer Reviewed
• [Journal Article] Analysis of microsatellite polymorphisms within the GLC1F locus in Japanese patients with normal tension glaucoma. (2010)
  • Author(s): Murakami K, et al
  • Journal Title: Mol Vis Volume: 16 Pages: 462-466
  • Peer Reviewed
• [Presentation] Genome-wide association studies on multifactorial ocular diseases (2011)
  • Author(s): Mizuki N
  • Organizer: 52nd Annual Meeting of Taiwan Ophthalmology Society
  • Place of Presentation: 台湾・台北(招待講演)
  • Year and Date: 2011-11-27
• [Presentation] Molecular Genetics of Behcet's disease (2011)
  • Author(s): Mizuki N, et al
  • Organizer: The 11th International Ocular Inflammation Society
  • Place of Presentation: インド・ゴア(招待講演)
  • Year and Date: 2011-11-14
• [Presentation] Behcet's disease : Role of regulatory T cells in disease remission (2011)
  • Author(s): Mizuki N, et al
  • Organizer: The 11th International Ocular Inflammation Society
  • Place of Presentation: インド・ゴア(招待講演)
  • Year and Date: 2011-11-14
• [Presentation] Contribution of the HLA-A region to genetic predisposition in Behcet's disease. (2010)
  • Author(s): Meguro A
  • Organizer: 14th International Conference on Behcet's Disease
  • Place of Presentation: イギリス・ロンドン(招待講演)
  • Year and Date: 2010-07-09