| Objective To investigate the associations of mitochondrial DNA（mt DNA）genetic variants with systemic lupus erythematosus（SLE）susceptibility,glucocorticoids（GCs）efficacy,and prognosis.Methods Our study was done in two stages.In the discovery stage,we performed whole mitochondrial genome sequencing using next-generation sequencing in 100 patients and100 controls to initially screen potential mt DNA genetic variants associated with disease susceptibility.In the replication stage,we validated the results in 505 SLE patients and504 normal controls.In total,605 SLE patients and 604 normal controls were included in the two-stage case-control study.To investigate the association of mt DNA variants and GCs efficacy in SLE patients,whole mitochondrial genome sequencing was undertaken in 100 SLE patients（50 GCs-sensitive and 50 GCs-insensitive）at the discovery stage to screen potential mt DNA genetic variants related to GCs efficacy.Subsequently,431 SLE patients were enrolled in the validation stage.We performed a 12-week follow-up study to assess the efficacy of GCs,and 412 patients completed the follow-up.A total of 512patients completed the two-stage efficacy study.Patients were followed up periodically to explore the relationship between mt DNA variants and SLE prognosis.We used disease relapse as the main prognostic index.Relapse was defined as an increase in SLEDAI score of≥4 from the previous visit.Interactions were detected through crossover analysis and logistic regression.Multifactor dimensionality reduction was applied to detect high-order interactions between mt DNA genetic variants and environmental factors.Results In the discovery stage,a total of nine mt DNA genetic variants（C151T,A4833G,T5108C,A8701G,A12358G,G12372A,G14569A,T15940del,CA514-515del）were screened to be disease-related,and we identified four mt DNA variants（T16362C,T16519C,302Ins C,302Ins CC）with suggestive evidence of association with GCs efficacy.For the replication stage,a total of four mt DNA variants（A4833G,T5108C,G14569A,CA514-515del）were validated to be related to SLE susceptibility.In the combined sample,these variants were more significantly associated with SLE(A4833G:OR=4.461,95%CI=2.136-9.315,Pcombined=6.863×10-5,PBH=2.745×10-4;T5108C:OR=4.155,95%CI=2.120-8.143,Pcombined=3.346×10-5,PBH=2.677×10-4;G14569A:OR=2.192,95%CI=1.286-3.736,Pcombined=0.004,PBH=0.011;CA514-515del:OR=0.744,95%CI=0.593-0.933,Pcombined=0.010,PBH=0.020).The combined discovery and replication analysis identified one mt DNA variant（T16362C）with association with the efficacy of GCs.Individuals carrying this variation had better response to GCs therapy(OR=0.587,95%CI=0.384-0.898,Pcombined=0.014,PBH=0.014).Gender stratification analysis showed that T16362C(OR=0.537,95%CI=0.341-0.847,Pcombined=0.007,PBH=0.011)and T16519C(OR=1.778,95%CI=1.197-2.643,Pcombined=0.004,PBH=0.011)were linked with GCs efficacy in females.In the prognosis study,mt DNA variants A4833G(adjusted HR=12.110,95%CI=2.676-54.795,P=0.001,PBH=0.003)and G14569A(adjusted HR=8.087,95%CI=2.729-23.964,P=1.624×10-4,PBH=9.744×10-4)substantially increased SLE relapse risk.When stratified by gender,an elevated relapse risk was detected among female patients harbouring the variant T5108C(adjusted HR=8.230,95%CI=1.886-35.920,P=0.005,PBH=0.010)and T16362C(adjusted HR=1.778,95%CI=1.126-2.807,P=0.014,PBH=0.021).Haplotype analysis showed that haplogroup G was linked with SLE susceptibility(adjusted OR=4.336,95%CI=2.073-9.072,P=9.791×10-5,PBH=0.001)and prognosis(adjusted HR=12.109,95%CI=2.676-54.787,P=0.001,PBH=0.013).Moreover,mt DNA genetic variant and environment factors interactions were observed.Conclusions We identified novel mt DNA genetic variants that were associated with SLE susceptibility,GCs efficacy,and prognosis.Interactions between mt DNA variants and environmental factors were related to SLE susceptibility and GCs efficacy.Our findings provide important information for future understanding of the occurrence and development of SLE from the perspective of mt DNA inheritance. |
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