Mitochondrial DNA genetic variants are associated with systemic lupus erythematosus susceptibility, glucocorticoids efficacy, and prognosis.

OBJECTIVE To investigate the associations of mitochondrial DNA (mtDNA) genetic variants with systemic lupus erythematosus (SLE) susceptibility, glucocorticoids (GCs) efficacy, and prognosis. METHODS Our study was done in two stages. First, we performed the whole mitochondrial genome sequencing in 100 patients and 100 controls to initially screen potential mtDNA variants associated with disease and glucocorticoids efficacy. Then, we validated the results in an independent set of samples. In total, 605 SLE patients and 604 normal controls were included in our two-stage study. A two-stage efficacy study was conducted in 512 patients treated with GCs for 12 weeks. We also explored the association between mtDNA variants and SLE prognosis. RESULTS In the combined sample, four mtDNA variants (A4833G, T5108C, G14569A, CA514-515-) were associated with SLE susceptibility (all P  BH<0.05). We confirmed that T16362C was related to GCs efficacy (P  BH=0.014). Significant associations were detected between T16362C and T16519C and the efficacy of GCs in females with SLE (P  BH<0.05). In the prognosis study, variants A4833G (P  BH=0.003) and G14569A (P  BH=9.744 × 1 0 -4) substantially increased SLE relapse risk. Female patients harbouring variants T5108C and T16362C were more prone to relapse (P  BH<0.05). Haplotype analysis showed that haplogroup G was linked with SLE susceptibility (P  BH=0.001) and prognosis (P  BH=0.013). Moreover, mtDNA variants-environment interactions were observed. CONCLUSION We identified novel mtDNA genetic variants that were associated with SLE susceptibility, GCs efficacy, and prognosis. Interactions between mtDNA variants and environmental factors were related to SLE risk and GCs efficacy. Our findings provide important information for future understanding the occurrence and development of SLE.