Association Study Of Mitochondrial DNA Copy Number With The Risk,Glucocorticoids Effectiveness And Prognosis Of Systemic Lupus Erythematosus

Objective This study aimed to investigate the association between mitochondrial DNA copy number（mt DNAcn）and the risk,glucocorticoids（GC）effectiveness,and the prognosis of systemic lupus erythematosus（SLE）,and its interactions with environmental factors and tumor necrosis factor receptor-associated protein 1（TRAP1）genetic polymorphisms.Methods In this study,595 patients with SLE and 603 healthy controls from the First and Second Affiliated Hospital of Anhui Medical University,were recruited based on a case-control study design.Real-time fluorescent quantitative PCR was used to quantify mt DNAcn of peripheral leukocytes,and the multiple SNa Pshot technique was used for TRAP1 genotyping.Follow-up studies were conducted on SLE patients who met the follow-up requirements in the case-control study.In the GC effectiveness follow-up study,we initially enrolled 515 patients with SLE,of whom 20 were lost to follow-up,and a total of 495 patients completed a 12-week follow-up of GC effectiveness.After 12 weeks of follow-up,the sensitivity of patients to GC treatment was assessed based on the SLE disease activity index.In the prognostic follow-up study,we included 324 SLE patients who followed for at least one year.The t test,Mann Whitney U test,Chi-square test,logistic regression,Kaplan-Meier survival analysis,and Cox proportional risk regression were used for statistical analysis.The possible interactions were analyzed by multiplicative and additive interaction analyses,and the multifactor dimensionality reduction method.Results The mt DNAcn of SLE was lower than healthy controls（68.72 vs.84.69;P<0.001）,and mt DNAcn was significantly associated with SLE(OR_adj=0.988,95%CI:0.985-0.992,P_adj<0.001).When grouping according to the median,tertile,and quartile distribution of mt DNAcn in controls,the results showed that the decrease in mtdnacn was significantly associated with an increased risk of SLE（P<0.05）.mt DNAcn was significantly lower in patients with renal disorder and thrombocytopenia than in patients without corresponding clinical manifestations（renal disorder:60.95 vs.71.72,P=0.007;thrombocytopenia:62.21 vs.72.75,P=0.003）.Logistic regression analysis showed that mt DNAcn levels were also statistically associated with renal disorder and thrombocytopenia（P<0.05）.In the follow-up study of GC effectiveness,no significant association was found between mt DNAcn and GC effectiveness.However,in the stratified analysis,it was found that the decrease of mt DNAcn was related to the insensitivity of GC in the subgroup of patients who consumed spicy foods or with arthritis.When patients were grouped according to their mt DNAcn quartile values,patients in the lowest quartile had a poorer response to GC compared to the highest quartile(spicy foods consumption subgroup:OR_adj=3.340,95%CI:1.376-8.110,P=0.008;arthritis subgroup:OR_adj=2.930,95%CI:1.054-8.147,P=0.039).In the prognostic follow-up study,the overall analysis showed that mt DNAcn was not associated with SLE prognosis.However,in the drinking subgroup,low mt DNAcn was associated with a reduced risk of recurrence of SLE（HR:0.080,95%CI:0.008-0.765;P=0.028）.Furthermore,mt DNAcn and sex,BMI,and TRAP1 genetic polymorphisms have multiplicative,additive,and high-order interactions on susceptibility,GC effectiveness,and prognosis of SLE.Conclusion The study suggests that low mt DNAcn is associated with an increased risk of SLE.Low mt DNAcn may reduce sensitivity to GC in subgroups of patients who consumed spicy foods or with arthritis.Individuals with lower mt DNAcn in drinking patients have a better prognosis.The interactions between mt DNAcn and TRAP1 gene polymorphisms may jointly affect the risk and GC effectiveness of SLE.