{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T04:44:12Z","timestamp":1782967452971,"version":"3.54.5"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,15]],"date-time":"2022-07-15T00:00:00Z","timestamp":1657843200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>Multiple sclerosis (MS) is a chronic inflammatory autoimmune and degenerative disorder of the central nervous system. Telomeres are protective structures located at the ends of linear chromosomes, and leukocyte telomere length (LTL) is closely connected with cell aging and senescence. However, the relationship between LTL and the risk of MS remains unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed a two-sample Mendelian randomization (MR) to evaluate whether LTL was causally associated with MS risk.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In our MR analysis, 12 LTL-related variants were selected as valid instrumental variables, and a causal relationship between LTL and MS was suggested. The risk of MS nearly doubled as the genetically predicted LTL shortened by one standard deviation (SD) under the inverse variance weighted (IVW) fixed effect model (odds ratio (OR) = 2.00, 95% confidence interval (CI): 1.52-2.62, <jats:italic>p<\/jats:italic> = 6.01e-07). Similar estimated causal effects were also observed under different MR models. The MR\u2013Egger regression test did not reveal any evidence of directional pleiotropy (intercept = -0.005, stand error (SE) = 0.03, <jats:italic>p<\/jats:italic> = 0.87). The Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) analysis also indicated no directional pleiotropy or outliers for any LTL-related IVs (<jats:italic>p<\/jats:italic>-global test = 0.13). In addition, a leave-one-out sensitivity analysis showed similar findings, which further emphasized the validity and stability of the causal relationship.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results suggest a potential causal effect of LTL on the risk of MS. Genetically predicted shorter LTL could increase the risk of MS in the European population. LTL should be noted and emphasized in the pathogenesis and treatment of MS.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.922922","type":"journal-article","created":{"date-parts":[[2022,7,15]],"date-time":"2022-07-15T15:15:36Z","timestamp":1657898136000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":35,"title":["A causal relationship between leukocyte telomere length and multiple sclerosis: A Mendelian randomization study"],"prefix":"10.3389","volume":"13","author":[{"given":"Qiao","family":"Liao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fa-Fa","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang-Fang","family":"Bi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(02)08220-X","article-title":"Multiple sclerosis","volume":"359","author":"Compston","year":"2002","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nrleng.2020.05.023","article-title":"Immunosenescence: the role of age in multiple sclerosis","author":"Ostolaza Ibanez","year":"2022","journal-title":"Neurologia (Engl Ed)"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1177\/1352458516634871","article-title":"Aging and multiple sclerosis","volume":"22","author":"Sanai","year":"2016","journal-title":"Mult Scler"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.706434","article-title":"The role of T cell senescence in neurological diseases and its regulation by cellular metabolism","volume":"12","author":"Fessler","year":"2021","journal-title":"Front Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1126\/science.aab3389","article-title":"Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection","volume":"350","author":"Blackburn","year":"2015","journal-title":"Science"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00492-5","article-title":"Switching and signaling at the telomere","volume":"106","author":"Blackburn","year":"2001","journal-title":"Cell"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-014-2274-1","article-title":"Patients with multiple sclerosis show increased oxidative stress markers and somatic telomere length shortening","volume":"400","author":"Guan","year":"2015","journal-title":"Mol Cell Biochem"},{"key":"B8","doi-asserted-by":"publisher","first-page":"103084","DOI":"10.1016\/j.msard.2021.103084","article-title":"What telomeres teach us about MS","volume":"54","author":"Miner","year":"2021","journal-title":"Mult Scler Relat Disord"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-021-02315-y","article-title":"Leukocyte telomere length in patients with multiple sclerosis and its association with clinical phenotypes","volume":"58","author":"Hecker","year":"2021","journal-title":"Mol Neurobiol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25592","article-title":"Telomere length is associated with disability progression in multiple sclerosis","volume":"86","author":"Krysko","year":"2019","journal-title":"Ann Neurol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.14336\/AD.2021.0106","article-title":"Systematic review of studies on telomere length in patients with multiple sclerosis","volume":"12","author":"Buhring","year":"2021","journal-title":"Aging Dis"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyab084","article-title":"The use of two-sample methods for mendelian randomization analyses on single large datasets","volume":"50","author":"Minelli","year":"2021","journal-title":"Int J Epidemiol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/j.ajhg.2020.02.006","article-title":"Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length","volume":"106","author":"Li","year":"2020","journal-title":"Am J Hum Genet"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-011-2182-9","article-title":"Design and cohort description of the InterAct project: an examination of the interaction of genetic and lifestyle factors on the incidence of type 2 diabetes in the EPIC study","volume":"54","author":"Langenberg","year":"2011","journal-title":"Diabetologia"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001647","article-title":"Gene-lifestyle interaction and type 2 diabetes: the EPIC interact case-cohort study","volume":"11","author":"Langenberg","year":"2014","journal-title":"PloS Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s10654-006-9096-8","article-title":"EPIC-heart: the cardiovascular component of a prospective study of nutritional, lifestyle and biological factors in 520,000 middle-aged participants from 10 European countries","volume":"22","author":"Danesh","year":"2007","journal-title":"Eur J Epidemiol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1038\/ng.2528","article-title":"Identification of seven loci affecting mean telomere length and their association with disease","volume":"45","author":"Codd","year":"2013","journal-title":"Nat Genet"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1101\/2020.08.10.244293","article-title":"The MRC IEU OpenGWAS data infrastructure","author":"Elsworth","year":"2020","journal-title":"bioRxiv"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.34408","article-title":"The MR-base platform supports systematic causal inference across the human phenome","volume":"7","author":"Hemani","year":"2018","journal-title":"Elife"},{"key":"B20","article-title":"Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility","volume":"365","year":"2019","journal-title":"Science"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2022.796933","article-title":"Vitamin d as a risk factor for multiple sclerosis: Immunoregulatory or neuroprotective","volume":"13","author":"Gombash","year":"2022","journal-title":"Front Neurol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000001165","article-title":"Effects of vitamin d and body mass index on disease risk and relapse hazard in multiple sclerosis: A mendelian randomization study","volume":"9","author":"Vandebergh","year":"2022","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.840158","article-title":"Smoking attributable risk in multiple sclerosis","volume":"13","author":"Manouchehrinia","year":"2022","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-022-11161-4","article-title":"Age-specific effects of childhood body mass index on multiple sclerosis risk","author":"Hone","year":"2022","journal-title":"J Neurol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kws435","article-title":"Plasma vitamin d biomarkers and leukocyte telomere length","volume":"177","author":"Liu","year":"2013","journal-title":"Am J Epidemiol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3390\/jcm11010076","article-title":"Effect of physical activity, smoking, and sleep on telomere length: A systematic review of observational and intervention studies","volume":"11","author":"Barragan","year":"2021","journal-title":"J Clin Med"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.exger.2015.11.019","article-title":"Body mass index and leukocyte telomere length dynamics among older adults: Results from the ESTHER cohort","volume":"74","author":"Muezzinler","year":"2016","journal-title":"Exp Gerontol"},{"key":"B28","article-title":"Telomere shortening and ageing of the immune system","author":"Kaszubowska","year":"2008","journal-title":"J Physiol Pharmacol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00652","article-title":"Expanding role of T cells in human autoimmune diseases of the central nervous system","volume":"8","author":"Pilli","year":"2017","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s12979-022-00273-0","article-title":"Telomerase deficiency reflects age-associated changes in CD4+ T cells","volume":"19","author":"Matthe","year":"2022","journal-title":"Immun Ageing"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.1.432","article-title":"Thymic export function and T cell homeostasis in patients with relapsing remitting multiple sclerosis","volume":"171","author":"Hug","year":"2003","journal-title":"J Immunol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"461304","DOI":"10.1155\/2011\/461304","article-title":"Multiple sclerosis: a disorder of altered T-cell homeostasis","volume":"2011","author":"Haegert","year":"2011","journal-title":"Mult Scler Int"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2022.790884","article-title":"Characterization of antigen-induced CD4+ T-cell senescence in multiple sclerosis","volume":"13","author":"Tomas-Ojer","year":"2022","journal-title":"Front Neurol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/bs.vh.2022.01.014","article-title":"Telomere length and vitamin B12","volume":"119","author":"Praveen","year":"2022","journal-title":"Vitam Horm"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3390\/biom11101510","article-title":"Genetic, environmental and lifestyle determinants of accelerated telomere attrition as contributors to risk and severity of multiple sclerosis","volume":"11","author":"Hecker","year":"2021","journal-title":"Biomolecules"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkm681","article-title":"DNA Damage, cellular senescence and organismal ageing: causal or correlative","volume":"35","author":"Chen","year":"2007","journal-title":"Nucleic Acids Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2010.04.004","article-title":"The telomere\/telomerase system in autoimmune and systemic immune-mediated diseases","volume":"9","author":"Georgin-Lavialle","year":"2010","journal-title":"Autoimmun Rev"},{"key":"B38","doi-asserted-by":"publisher","first-page":"102699","DOI":"10.1016\/j.jaut.2021.102699","article-title":"Telomeres: New players in immune-mediated inflammatory diseases","volume":"123","author":"Heba","year":"2021","journal-title":"J Autoimmun"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2020-215918","article-title":"Peripheral blood leucocyte telomere length is associated with progression of interstitial lung disease in systemic sclerosis","volume":"76","author":"Liu","year":"2021","journal-title":"Thorax"},{"key":"B40","doi-asserted-by":"publisher","first-page":"577187","DOI":"10.1016\/j.jneuroim.2020.577187","article-title":"Association between shorter leukocyte telomeres and multiple sclerosis","volume":"341","author":"Habib","year":"2020","journal-title":"J Neuroimmunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1177\/1352458514561906","article-title":"Chitinase 3-like proteins as diagnostic and prognostic biomarkers of multiple sclerosis","volume":"21","author":"Hinsinger","year":"2015","journal-title":"Mult Scler"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000815","article-title":"CSF chitinase 3-like-1 association with disability of primary progressive MS","volume":"7","author":"Perez-Miralles","year":"2020","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.53.8.1876","article-title":"Cerebrospinal fluid isoprostane shows oxidative stress in patients with multiple sclerosis","volume":"53","author":"Greco","year":"1999","journal-title":"Neurology"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1023\/A:1007608615682","article-title":"Isoprostanes, novel markers of oxidative injury, help understanding the pathogenesis of neurodegenerative diseases","volume":"25","author":"Greco","year":"2000","journal-title":"Neurochem Res"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1139\/cjpp-2018-0246","article-title":"Vitamin e administration erases an enhanced oxidation in multiple sclerosis","volume":"96","author":"Guan","year":"2018","journal-title":"Can J Physiol Pharmacol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyw220","article-title":"Assessing the suitability of summary data for two-sample mendelian randomization analyses using MR-egger regression: the role of the I2 statistic","volume":"45","author":"Bowden","year":"2016","journal-title":"Int J Epidemiol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.922922\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,15]],"date-time":"2022-07-15T15:15:40Z","timestamp":1657898140000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.922922\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,15]]},"references-count":46,"alternative-id":["10.3389\/fimmu.2022.922922"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.922922","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,15]]},"article-number":"922922"}}