Journal Article

Identification of Disease-Promoting HLA Class I and Protective Class II Modifiers in Japanese Patients with Familial Mediterranean Fever

Eguchi, Katsumi, Nakamura, Minoru, Yazaki, Masahide, Nakamura, Tadashi, Nakamura, Hitomi, Ida, Hiroaki, Kawakami, Atsushi, Furukawa, Hiroshi, Migita, Kiyoshi, Kishida, Dai, Toma, Tomoko, Masumoto, Junya, Koga, Tomohiro, Yasunami, Michio, Agematsu, Kazunaga, Nakamura, Akinori, Yachie, Akihiro

2015

Overview

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. 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. 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). The differential effects of HLA class I and class II polymorphisms were identified for Japanese FMF even in those with high-penetrance MEFV mutations.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Abdomen / Adolescent / Adult / Alleles / Asian Continental Ancestry Group - genetics / Care and treatment / Child / Clinical medicine / Colchicine / Complications and side effects / Cytoskeletal Proteins - genetics / Drb1 protein / Familial Mediterranean fever / Familial Mediterranean Fever - epidemiology / Familial Mediterranean Fever - genetics / Female / Fever / Genes / Genes, MHC Class I / Genetic aspects / Genetic polymorphisms / Genotype / Genotypes / Histocompatibility antigen HLA / HLA antigens / HLA-B Antigens - genetics / HLA-DRB1 Chains - genetics / Hospitals / Humans / Internal medicine / Japan - epidemiology / Male / Medicine / Middle Aged / Mutation / Neurology / Pathogenesis / Patients / Pediatrics / Periodic disease / Phenotypes / Polymorphism, Genetic / Pyrin / Pyrin protein / Rheumatoid arthritis / Rheumatology / Risk / Statistical analysis / Statistical tests / Studies / Surveillance / Young Adult