Telomere Length and Development of Systemic Lupus Erythematosus: A Mendelian Randomization Study.

OBJECTIVE: Previous observational studies demonstrated that a subset of patients with systemic lupus erythematosus (SLE) have markedly short telomere length in leukocytes. This study was undertaken to test whether leukocyte telomere length is causally associated with risk of SLE. METHODS: A 2-sample Mendelian randomization (MR) analysis was conducted to estimate causality of telomere length on SLE in European populations. A replication 2-sample MR study using Asian genetic data was also conducted. A reverse MR analysis was then performed to test the effects of SLE on telomere length. The autoantibodies targeting telomere-associated protein (telomeric repeat-binding factor 1 [TERF1] autoantibodies) were detected in patients with SLE, healthy controls, and patients with rheumatoid arthritis. RESULTS: The results of the inverse variance-weighted method (odds ratio [OR] 2.96 [95% confidence interval (95% CI) 1.58-5.55], P < 0.001) showed strong evidence for a causal relationship between longer telomere length and risk of SLE in people with European ancestry. The outcomes of MR-Egger regression analysis (OR 29.46 [95% CI 3.02-287.60], P = 0.033) and MR pleiotropy residual sum and outlier analysis (OR 3.62 [95% CI 2.03-6.46], P = 0.002) also showed that longer telomere length was significantly associated with increased risk of SLE in a European population. Sensitivity analyses using different methods and summary data sets showed that the results were still broadly consistent. A replication MR study using Asian genetic data yielded similar findings. However, the reverse MR analysis showed that genetically predicted SLE was not causally associated with telomere length. In addition, we found that TERF1 autoantibodies were present in 2 of 40 SLE patients (5.0%). CONCLUSION: In contrast with previous observational studies, MR analyses show that longer telomere length is significantly associated with increased risk of SLE.

Discovery of new serum biomarker panels for systemic lupus erythematosus diagnosis.

OBJECTIVE: Clinical diagnosis of SLE is currently challenging due to its heterogeneity. Many autoantibodies are associated with SLE and are considered potential diagnostic markers, but systematic screening and validation of such autoantibodies is lacking. This study aimed to systematically discover new autoantibodies that may be good biomarkers for use in SLE diagnosis. METHODS: Sera from 15 SLE patients and 5 healthy volunteers were analysed using human proteome microarrays to identify candidate SLE-related autoantibodies. The results were validated by screening of sera from 107 SLE patients, 94 healthy volunteers and 60 disease controls using focussed arrays comprised of autoantigens corresponding to the identified candidate antibodies. Logistic regression was used to derive and validate autoantibody panels that can discriminate SLE disease. Extensive ELISA screening of sera from 294 SLE patients and 461 controls was performed to validate one of the newly discovered autoantibodies. RESULTS: A total of 31, 11 and 18 autoantibodies were identified to be expressed at significantly higher levels in the SLE group than in the healthy volunteers, disease controls and healthy volunteers plus disease control groups, respectively, with 25, 7 and 13 of these differentially expressed autoantibodies being previously unreported. Diagnostic panels comprising anti-RPLP2, anti-SNRPC and anti-PARP1, and anti-RPLP2, anti-PARP1, anti-MAK16 and anti- RPL7A were selected. Performance of the newly discovered anti-MAK16 autoantibody was confirmed by ELISA. Some associations were seen with clinical characteristics of SLE patients, such as disease activity with the level of anti-PARP1 and rash with the level of anti-RPLP2, anti-MAK16 and anti- RPL7A. CONCLUSION: The combined autoantibody panels identified here show promise for the diagnosis of SLE and for differential diagnosis of other major rheumatic immune diseases.