title: Aggregation of rare/low-frequency variants of the mitochondria respiratory chain-related proteins in rheumatoid arthritis patients.
abstract: Exome sequencings were conducted using 59 patients having rheumatoid arthritis (RA) and 93 controls. After stepwise filtering, 107 genes showed less than 0.05 of P-values by gene-burden tests. Among 107 genes, NDUFA7 which is a subunit of the complex I in the mitochondrial respiratory chain was selected for further analysis based on previous reports. A case-control study was performed on the three single-nucleotide variants (SNVs) of NDUFA7 with 432 cases and 432 controls. An association was observed between NDUFA7 and RA with severe erosive arthritis. These results together with previous reports suggested the involvement of reactive oxygen species (ROS) in the pathogenesis of RA. In the next step, four SNVs from three genes related to the mitochondrial respiratory chain were selected, which is a major source of ROS, and conducted a case-control study. An association was observed based on a pathway-burden test comprising NDUFA7, SDHAF2, SCO1 and ATP5O: P=1.56E-04, odds ratio=2.16, 95% confidence interval=1.43-3.28. Previous reports suggested the involvement of ROS in the pathogenesis of RA. The aggregation of SNVs in the mitochondria respiratory chain suggests the pivotal role of those SNVs in the pathogenesis of RA with severe erosive arthritis.
authors.affiliation: Department of Molecular Life Sciences, Division of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Mitsunaga
authors.affiliation: Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Japan.|Department of Bioinformatics and Genomics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Hosomichi
authors.affiliation: Department of Molecular Life Sciences, Division of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Okudaira
authors.affiliation: Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nakaoka
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan.|Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Kuwana
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Sato
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kaneko
authors.affiliation: Department of Clinical Health Science, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Homma
authors.affiliation: The Institute of Medical Science, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Oka
authors.affiliation: Department of Molecular Life Sciences, Division of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shiina
authors.affiliation: Department of Molecular Life Sciences, Division of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Inoko
authors.affiliation: Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Japan.
authors.forename: Ituro
authors.initials: I
authors.lastname: Inoue
mesh_terms: D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D004579:Electron Transport / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D024101:Mitochondrial Proteins