title: Identification of Disease-Promoting HLA Class I and Protective Class II Modifiers in Japanese Patients with Familial Mediterranean Fever.
abstract: OBJECTIVE
  The genotype-phenotype correlation of MEFV remains unclear for the familial Mediterranean fever (FMF) patients, especially without canonical MEFV mutations in exon 10. The risk of FMF appeared to be under the influence of other factors in this case. The contribution of HLA polymorphisms to the risk of FMF was examined as strong candidates of modifier genes.
  
  
  METHODS
  Genotypes of HLA-B and -DRB1 loci were determined for 258 mutually unrelated Japanese FMF patients, who satisfied modified Tel-Hashomer criteria, and 299 healthy controls. The effects of carrier status were evaluated for the risk of FMF by odds ratio (OR). The HLA effects were also assessed for clinical forms of FMF, subsets of FMF with certain MEFV genotypes and responsiveness to colchicine treatment.
  
  
  RESULTS
  The carriers of B*39:01 were increased in the patients (OR = 3.25, p = 0.0012), whereas those of DRB1*15:02 were decreased (OR = 0.45, p = 0.00050), satisfying Bonferroni's correction for multiple statistical tests (n = 28, p<0.00179). The protective effect of DRB1*15:02 was completely disappeared in the co-existence of B*40:01. The HLA effects were generally augmented in the patients without a canonical MEFV variant allele M694I, in accordance with the notion that the lower penetrance of the mutations is owing to the larger contribution of modifier genes in the pathogenesis, with a few exceptions. Further, 42.9% of 14 colchicine-resistant patients and 13.5% of 156 colchicine-responders possessed B*35:01 allele, giving OR of 4.82 (p = 0.0041).
  
  
  CONCLUSIONS
  The differential effects of HLA class I and class II polymorphisms were identified for Japanese FMF even in those with high-penetrance MEFV mutations.
authors.affiliation: Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Yasunami
authors.affiliation: Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Department of Infection and Host Defense, Graduate School of Medicine, Shinshu University, Matsumoto, Japan.
authors.forename: Kazunaga
authors.initials: K
authors.lastname: Agematsu
authors.affiliation: Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Nakamura
authors.affiliation: Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Yazaki
authors.affiliation: Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Kishida
authors.affiliation: Department of Pediatrics, Kanazawa University, Kanazawa, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yachie
authors.affiliation: Department of Pediatrics, Kanazawa University, Kanazawa, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toma
authors.affiliation: Department of Pathogenomics, Ehime University Graduate School of Medicine, To-on, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Masumoto
authors.affiliation: Department of Rheumatology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ida
authors.affiliation: First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Koga
authors.affiliation: First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kawakami
authors.affiliation: Department of Rheumatology, Sasebo City General Hospital, Sasebo, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Eguchi
authors.affiliation: Department of Rheumatology, National Hospital Organization Sagamihara Hospital, Sagamihara, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Furukawa
authors.affiliation: Department of Rheumatology, Kumamoto Shinto General Hospital, Kumamoto, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Omura, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Omura, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Migita
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics; D002648:Child; D003598:Cytoskeletal Proteins / Q000235:genetics*; D010505:Familial Mediterranean Fever / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005805:Genes, MHC Class I; D005838:Genotype; D015235:HLA-B Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D000071198:Pyrin; D055815:Young Adult
chemical_list: D003598:Cytoskeletal Proteins; D015235:HLA-B Antigens; D059811:HLA-DRB1 Chains; C000604192:MEFV protein, human; D000071198:Pyrin