Germline and somatic mtDNA mutation spectrum of rheumatoid arthritis patients in the Taizhou area, China.

Objective: Reactive oxygen species are believed to be involved in the onset of RA, and the association between nuclear-encoded mitochondrial respiratory chain-related variants and RA has recently been revealed. However, little is known about the landscape of mitochondrial DNA (mtDNA) variants in RA.

Methods: Next-generation sequencing was conducted to profile mtDNA germline and somatic variants in 124 RA patients and 123 age- and sex-matched healthy controls in the Taizhou area, China. Fisher's exact test, SKAT and SKAT-O were used for gene-burden tests to investigate RA-related variants of mitochondrial genes. Predictive tools were applied to evaluate the pathogenicity of mtDNA variants, and mtDNA haplogroups were assigned according to mtDNA mutations recorded in PhyloTree database. The frequency distribution of mtDNA haplogroups between the groups was compared using χ2 analysis.

Results: We identified 467 RA-unique and 341 healthy control-unique mtDNA variants, with 443 common variants. Only MT-ATP6 with a significant burden of variants was identified by Fisher's exact test, SKAT and SKAT-O, even after Bonferroni adjustment, and the enrichment variants in MT-ATP6 was mainly driven by m.8830C>A, m.8833G>C and m.8843T>A variants. Besides, four frequently low-heteroplasmic variants including the three variants above and m.14135T>G of MT-ND5 were detected in RA only; except for m.8830C>A, they are considered potential pathogenicity based on functional predictions. χ2 analysis before Bonferroni adjustment revealed haplogroup F1/F1a to be negatively associated with RA (P < 0.05).

Conclusion: These results profiled the landscape of germline and somatic mtDNA variants in RA and supported the effects of mitochondrial genes on RA.