Mendelian randomization study on the association between telomere length and 10 common musculoskeletal diseases

doi:10.12307/2025.221

Abstract

Abstract: BACKGROUND: Multiple observational studies have suggested a potential association between telomere length and musculoskeletal diseases. However, the underlying mechanisms remain unclear.
OBJECTIVE: To investigate the genetic causal relationship between telomere length and musculoskeletal diseases using two-sample Mendelian randomization analysis.
METHODS: Genome-wide association study summary data of telomere length were obtained from the UK Biobank. Genome-wide association study summary data of 10 common musculoskeletal diseases (osteonecrosis, osteomyelitis, osteoporosis, rheumatoid arthritis, low back pain, spinal stenosis, gout, scapulohumeral periarthritis, ankylosing spondylitis and deep venous thrombosis of lower limbs) were obtained from the FinnGen consortium. Inverse variance weighting, Mendelian randomization-Egger and weighted median methods were used to evaluate the causal relationship between telomere length and 10 musculoskeletal diseases. Inverse variance weighting was the primary Mendelian randomization analysis method, and sensitivity analysis was performed to explore the robustness of the results.
RESULTS AND CONCLUSION: (1) Inverse variance-weighted results indicated a negative causal relationship between genetically predicted telomere length and rheumatoid arthritis (odds ratio=0.78, 95% confidence interval: 0.64-0.95, P=0.015) and osteonecrosis (odds ratio=0.56, 95% confidence interval: 0.36-0.90, P=0.016). No causal relationship was found between telomere length and the other eight musculoskeletal diseases (all P > 0.05). (2) Sensitivity analysis affirmed the robustness of these causal relationships, and Mendelian randomization-Egger intercept analysis found no evidence of potential horizontal pleiotropy (all P > 0.05). (3) This Mendelian randomized study supports that telomere length has protective effects against rheumatoid arthritis and osteonecrosis. However, more basic and clinical research will be needed to support our findings in the future.

Key words: telomere length">, musculoskeletal disease">, Mendelian randomization">, genome-wide association study">, single nucleotide polymorphism">, causal relationship">, instrumental variable

CLC Number:

Luo Weidong, Pu Bin, Gu Peng, Huang Feng, Zheng Xiaohui, Chen Fuhong. Mendelian randomization study on the association between telomere length and 10 common musculoskeletal diseases[J]. Chinese Journal of Tissue Engineering Research, 2025, 29(3): 654-660.

Figures/Tables 2

References

[1] MADAN I, GRIME PR. The management of musculoskeletal disorders in the workplace. Best Pract Res Clin Rheumatol. 2015;29(3):345-355.
[2] SAFIRI S, KOLAHI AA, CROSS M, et al. Prevalence, deaths, and disability-adjusted life years due to musculoskeletal disorders for 195 countries and territories 1990-2017. Arthritis Rheumatol. 2021; 73(4):702-714.
[3] LOPEZ-OTIN C, BLASCO MA, PARTRIDGE L, et al. The hallmarks of aging. Cell. 2013; 153(6):1194-1217.
[4] HAYCOCK PC, HEYDON EE, KAPTOGE S, et al. Leucocyte telomere length and risk of cardiovascular disease: systematic review and meta-analysis. BMJ. 2014;349:g4227.
[5] ZHAO J, MIAO K, WANG H, et al. Association between telomere length and type 2 diabetes mellitus: a meta-analysis. PLoS One. 2013; 8(11):e79993.
[6] RODE L, NORDESTGAARD BG, BOJESEN SE. Peripheral blood leukocyte telomere length and mortality among 64, 637 individuals from the general population. J Natl Cancer Inst. 2015;107(6):djv074.
[7] NIELSEN BR, LINNEBERG A, BENDIX L, et al. Association between leukocyte telomere length and bone mineral density in women 25-93 years of age. Exp Gerontol. 2015;66: 25-31.
[8] TAO L, HUANG Q, YANG R, et al. The age modification to leukocyte telomere length effect on bone mineral density and osteoporosis among Chinese elderly women. J Bone Miner Metab. 2019;37(6): 1004-1012.
[9] HARBO M, DELAISSE JM, KJAERSGAARD-ANDERSEN P, et al. The relationship between ultra-short telomeres, aging of articular cartilage and the development of human hip osteoarthritis. Mech Ageing Dev. 2013;134(9):367-372.
[10] BAYLIS D, NTANI G, EDWARDS MH, et al. Inflammation, telomere length, and grip strength: a 10-year longitudinal study. Calcif Tissue Int. 2014;95(1):54-63.
[11] SEKULA P, DEL GRECO MF, PATTARO C, et al. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol. 2016;27(11):3253-3265.
[12] GREEN HD, JONES A, EVANS JP, et al. A genome-wide association study identifies 5 loci associated with frozen shoulder and implicates diabetes as a causal risk factor. PLoS Genet. 2021;17(6):e1009577.
[13] LOH PR, KICHAEV G, GAZAL S, et al. Mixed-model association for biobank-scale datasets. Nat Genet. 2018;50(7):906-908.
[14] GIBSON MJ, SPIGA F, CAMPBELL A, et al. Reporting and methodological quality of studies that use Mendelian randomisation in UK Biobank: a meta-epidemiological study. BMJ Evid Based Med. 2023;28(2):103-110.
[15] CODD V, DENNIFF M, SWINFIELD C, et al. Measurement and initial characterization of leukocyte telomere length in 474, 074 participants in UK Biobank. Nat Aging. 2022;2(2):170-179.
[16] SHIM H, CHASMAN DI, SMITH JD, et al. A multivariate genome-wide association analysis of 10 LDL subfractions, and their response to statin treatment, in 1868 Caucasians. PLoS One. 2015;10(4): e0120758.
[17] BORENSTEIN M, HEDGES LV, HIGGINS JP, et al. A basic introduction to fixed-effect and random-effects models for meta-analysis. Res Synth Methods. 2010;1(2):97-111.
[18] BOWDEN J, DEL GRECO MF, MINELLI C, et al. Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption. Int J Epidemiol. 2019;48(3):728-742.
[19] HARTWIG FP, DAVEY SMITH G, BOWDEN J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol. 2017;46(6):1985-1998.
[20] BOWDEN J, DAVEY SMITH G, BURGESS S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015;44(2):512-525.
[21] HEMANI G, ZHENG J, ELSWORTH B, et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife. 2018;7:e34408.
[22] COLMEGNA I, DIAZ-BORJON A, FUJII H, et al. Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis. Arthritis Rheum. 2008;58(4):990-1000.
[23] TAMAYO M, MOSQUERA A, REGO JI, et al. Differing patterns of peripheral blood leukocyte telomere length in rheumatologic diseases. Mutat Res. 2010;683(1-2):68-73.
[24] GAMAL RM, HAMMAM N, ZAKARY MM, et al. Telomere dysfunction-related serological markers and oxidative stress markers in rheumatoid arthritis patients: correlation with diseases activity. Clin Rheumatol. 2018;37(12):3239-3246.
[25] LEE YH, BAE SC. Association between shortened telomere length and rheumatoid arthritis: a meta-analysis. Z Rheumatol. 2018;77(2):160-167.
[26] ZENG Z, ZHANG W, QIAN Y, et al. Association of telomere length with risk of rheumatoid arthritis: a meta-analysis and Mendelian randomization. Rheumatology (Oxford). 2020;59(5):940-947.
[27] WAGNER CL, HANUMANTHU VS, TALBOT CC JR., et al. Short telomere syndromes cause a primary T cell immunodeficiency. J Clin Invest. 2018;128(12):5222-5234.
[28] RODIER F, COPPE JP, PATIL CK, et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. 2009;11(8): 973-979.
[29] YADAV S, MAURYA PK. Correlation between telomere length and biomarkers of oxidative stress in human aging. Rejuvenation Res. 2022;25(1):25-29.
[30] LEE SW, LIM KH, LEE KJ, et al. No association between telomere length and osteonecrosis of the femoral head. BMC Musculoskelet Disord. 2021;22(1):176.
[31] DJORDJEVIC K, MILOJEVIC SAMANOVIC A, VESELINOVIC M, et al. Oxidative stress mediated therapy in patients with rheumatoid arthritis: a systematic review and meta-analysis. Antioxidants (Basel). 2023;12(11):1938.
[32] POONPET T, SAETAN N, TANAVALEE A, et al. Association between leukocyte telomere length and angiogenic cytokines in knee osteoarthritis. Int J Rheum Dis. 2018;21(1):118-125.
[33] WANG H, CHEN Q, LEE SH, et al. Impairment of osteoblast differentiation due to proliferation-independent telomere dysfunction in mouse models of accelerated aging. Aging Cell. 2012;11(4):704-713.
[34] WILLEIT P, WILLEIT J, BRANDSTATTER A, et al. Cellular aging reflected by leukocyte telomere length predicts advanced atherosclerosis and cardiovascular disease risk. Arterioscler Thromb Vasc Biol. 2010; 30(8):1649-1656.
[35] SANDERS JL, CAULEY JA, BOUDREAU RM, et al. Leukocyte telomere length is not associated with BMD, osteoporosis, or fracture in older adults: results from the health, aging and body composition study. J Bone Miner Res. 2009;24(9):1531-1536.
[36] DENG S, LIU S, XU S, et al. Shorter telomere length in peripheral blood leukocytes is associated with post-traumatic chronic osteomyelitis. Surg Infect (Larchmt). 2020;21(9):773-777.
[37] LE MAITRE CL, FREEMONT AJ, HOYLAND JA. Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration. Arthritis Res Ther. 2007;9(3):R45.
[38] DECHSUPA S, YINGSAKMONGKOL W, LIMTHONGKUL W, et al. Relative telomere length and oxidative DNA damage in hypertrophic ligamentum flavum of lumbar spinal stenosis. PeerJ. 2018;6:e5381.
[39] KALSON NS, BROCK TM, MANGINO M, et al. Reduced telomere length is associated with fibrotic joint disease suggesting that impaired telomere repair contributes to joint fibrosis. PLoS One. 2018;13(1):e0190120.
[40] VAZIRPANAH N, KIENHORST LBE, VAN LOCHEM E, et al. Patients with gout have short telomeres compared with healthy participants: association of telomere length with flare frequency and cardiovascular disease in gout. Ann Rheum Dis. 2017; 76(7):1313-1319.
[41] QI M, YU J, PING F, et al. Leukocyte telomere length independently predicts hyperuricemia risk in a longitudinal study of the Chinese population. Nutr Metab Cardiovasc Dis. 2024;34(1):230-234.
[42] TAMAYO M, PERTEGA S, MOSQUERA A, et al. Individual telomere length decay in patients with spondyloarthritis. Mutat Res. 2014;765:1-5.