Telomere Length And Development Of Systemic Lupus Erythematosus: A Mendelian Randomization Study

ObjectiveSystemic lupus erythematosus（SLE）is one of the most representative autoimmune diseases on account of the complicated clinical manifestations as well as the prolonged and lingering course of disease.Our current research was aimed to assess the association between telomere length（TL）and SLE and evaluate the causal effect of TL on SLE.MethodsWe performed a meta-analysis through document retrieval to estimate the pooled effect of TL on SLE patients and controls by calculating standardized mean differences（SMDs）with 95%confidence interval（CI）along with random effects model.Publication bias between studies was assessed by plotting funnel plots,Begg’s and Egger’s tests.Heterogeneity analysis was used to examine heterogeneity between researches and subgroup analysis and meta regression method was applied to explore potential sources of heterogeneity between studies.Then,seven significant single-nucleotide polymorphisms（SNPs）（rs10936599,rs9420907,rs2736100,rs7675998,rs8105767,rs755017 and rs2967374）related to TL(P<5×10^-08)were collected as instrumental variables（IVs）from a genome-wide association（GWAS）study in people with European ethnicity,and these SNPs were also reviewed from another separate SLE GWAS study involving 5201 SLE cases with 9066 healthy controls with European descent.Two-sample Mendelian randomization（TSMR）analysis including weighted median,weighted mode,inverse-variance weighed（IVW）,MR-Egger regression and MR-PRESSO（MR Pleiotropy RESidual Sum and Outlier）approaches was applied to estimate causality of TL on SLE in the European population.In the further research,we validated the above results of TSMR analysis targeted at the European population in the Asian population with the same analytical method.Besides,our current research detected the presence of TERF1 autoantibodies in SLE patients.ResultsTen independent studies including 361 SLE patients and 349 healthy controls showed that SLE patients had shorter TL compared to the control group[SMD-1.570（95%CI-2.409,-0.731）,P<0.001].Symmetrical funnel plots and Begg’s（P=0.09）and Egger’s（P=0.128）tests showed that there was no publication bias among the studies.There was heterogeneity between studies（I~2=95%,P<0.01）and sample size（P=0.032）,sample source（P<0.001）and method of measuring TL（P<0.001）may be potential sources of heterogeneity between researches.Results of the IVW method[odds ratio（OR）2.96（95%CI 1.58,5.55）,P<0.001]showed strong evidence for casual relationship between TL and risk of SLE in people with European ancestry.And the outcomes of MR-Egger regression[OR 29.46（95%CI 3.02,287.60）,P=0.033],weighted median[OR 3.75（95%CI 2.26,6.21）,P<0.001],weighted mode[OR 3.66（95%CI 2.29,5.87）,P=0.002]and MR-PRESSO（P=0.002）approaches also suggested there was significant casual relation of TL to genetic susceptibility of SLE.And sensitivity analyses using different methods showed that the results are consistent and robust.Similarly,the further validation research on population of Asian descent also presented obvious causality of TL on risk of SLE.What’s more,our study found that TERF1 antibody was detected in the plasma of SLE patients and was present in 2/40（5%）of SLE patients.ConclusionsThe Outcomes of our meta-analysis on traditional observational studies showed that compared with healthy controls,TL was significantly shortened in SLE patients.On the contrary,the present MR research found that in European and Asian populations,long TL could significantly increase the risk of SLE.More explorations are needed to provide supporting evidence for this study in the future.