Association of peripheral blood mitochondrial DNA gene variation and methylation levels with rheumatoid arthritis

Mitochondrial dysfunction is closely related to the pathogenesis of various autoimmune diseases, and mitochondrial DNA (mtDNA) gene variations are associated with the susceptibility to autoimmune diseases. This study aimed to investigate association between mtDNA genetic variants, methylation levels and rheumatoid arthritis (RA).

We performed mtDNA whole genome sequencing in 32 RA patients and 32 controls, and then validated 8 mtDNA variants using the SNaPshot™ multiplex technique in 452 RA patients and 457 controls. The methylation levels of 4 mtDNA genes were measured in 108 RA patients and 107 controls by MethylTarget technique.

We found that ND5 gene m.12705 T genotype, tRNA-Pro gene m.16304C genotype, tRNA-Pro gene m.16319 A genotype were significantly associated with RA susceptibility in entire population and female population. Moreover, the increased frequency of m.12705 T and the decreased frequency of m.16304C were significantly related to anti-CCP positive in RA patients. While tRNA-Pro gene m.16092 T > C, m.16189 T > C, RNR2 gene m.2706 T > G, ND2 gene m.4833 A > G, m.5108 T > C showed no association with the risk of RA. When compared to controls, the methylation levels of ND5, RNR2, ND2 genes were significantly decreased in RA patients. In addition, ND5, RNR2 methylation levels were linked to erythrocyte sedimentation rate, and m.12705C > T variant significantly influenced ND5 methylation level among RA patients.

Multiple mtDNA variants in ND5, tRNA-Pro genes and methylation levels of ND5, RNR2, ND2 genes were significantly associated with genetic susceptibility to RA in Chinese population.