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.

Identification of rare coding variants in TYK2 protective for rheumatoid arthritis in the Japanese population and their effects on cytokine signalling

“…TYK2 is a member of the JAK family of proteins, which also includes JAK1, JAK2 and JAK3. A previous study has indicated that three common variants, I684S, A928A and P1104A, in TYK2 are protective in the pathogenesis of RA,36 40 but the accumulation of rare missense variants in TYK2 has not been significant 24–26 40. Our results showed that rare coding variants in TYK2 protected against the onset of RA in the Japanese population.…”

“…This strategy worked well to pinpoint likely causal genes in other diseases, for example, IFIH1 in type 1 diabetes,18 interleukin (IL)-23 receptor in inflammatory bowel disease,19 MTNR1B in type 2 diabetes,20 PLD3 in Alzheimer’s disease,21 CARD9 and RNF186 in ulcerative colitis,22 and multigenic modules in Crohn’s disease 23. Several studies have applied this strategy to RA and have reported associations between RA and IL2R ,24 VSTM1 25 and the mitochondrial respiratory chain pathway 26. To identify rare variants in genes with relevant biological functions,24 25 large sample sizes are required to detect their signals.…”

Mitochondrial haplogroups in patients with rheumatoid arthritis: No association with disease and disease manifestations

“…An imbalance between ROS production and elimination is thought to lead to the oxidative stress in RA patients which contributes to tissue damage and further to the chronicity of the disease [ 26 ]. Oxidative stress has therefore been considered to be involved in the onset of RA [ 15 , 26 – 29 ].…”

“…A study by Mitsunaga et al found a significant association between severe erosive RA and mitochondrial respiratory complex-related genes, that were major site of ROS generation [ 15 ]. They suggested that ROS were involved in cartilage and bone destruction through activation of osteoclast and fibroblast-like synoviocytes [ 15 ].…”

“…Rheumatoid arthritis (RA) is a chronic auto-immune disorder which is characterized by synovial inflammation and hyperplasia, autoantibody production, cartilage and bone destruction leading to erosions and joint deformity [ 14 ]. A recent study has suggested ROS to be involved in the pathogenesis of RA [ 15 ], but whether this relates to associations between RA and the mtDNA hgs have not previously been investigated. The aim of this study was to analyse the distribution of mtDNA hgs in a cohort of patients with RA according to disease phenotype, presence of rheumatoid factor, and biological treatment.…”