Aggregation of rare/low-frequency variants of the mitochondria respiratory chain-related proteins in rheumatoid arthritis patients

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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.

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We thank the DNA donors and supporting medical staff for making this study possible. We thank Miyako Nakagawa and Tomomi Ito (Division of Rheumatology, Tokai University School of Medicine), Masayuki Tanaka and Hideki Hayashi (Department of Bioinformatics, Support Center for Medical Research and Education, Tokai University) for their excellent technical assistance. We also thank Dr Atsushi Toyoda (Comparative Genomics Laboratory, National Institute of Genetics), Dr Shoji Tsuji, Dr Jun Mitsui and Dr Hiroyuki Ishiura (Department of Neurology, Division of Neuroscience, Graduate School of Medicine, The University of Tokyo), Dr Shinichi Morishita and Dr Jun Yoshimura (Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo) for their supporting based on the Grant in-Aid-for Scientific Research on Innovative Areas ‘Genome Science’ (No.221S0002) from Ministry of Education, Culture, Sports, Science and Technology of Japan. This work was supported in part by, a Grant in-Aid-for Scientific Research on Innovative Areas ‘Genome Science’ (No.221S0002) from Ministry of Education, Culture, Sports, Science and Technology of Japan and a Grant-in-Aid for Scientific Research from the Japanese Ministry of Health, Labour and Welfare.

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Correspondence to Ituro Inoue.

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