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image of The Causal Effects of Lifestyle Factors on Osteoarthritis: A Two-sample Mendelian Randomisation Study

Abstract

Background

Modern sedentary lifestyles are prevalent among individuals with osteoarthritis. However, direct evidence linking such behaviours as causative factors of osteoarthritis remain limited due to the presence of confounding variables.

Objective

This study aims to determine the extent to which lifestyle factors have causal effects on osteoarthritis through a two-sample Mendelian randomisation (MR) study.

Methods

Exposure-outcome relationships were evaluated using inverse variance weighted two-sample MR and summary statistics of genome-wide association studies of lifestyle factors and osteoarthritis. Weighted median, MR-PRESSO, and MR-Egger regression were used as sensitivity analyses. We obtained causality estimates, 95% confidence intervals (CI), and P-values from each MR method. Steiger filtering and radial filtering were used to exclude SNPs demonstrating reverse causality and significant heterogeneity, respectively.

Results

MR analyses demonstrated that certain lifestyle factors had causal effects on osteoarthritis, particularly insomnia (OR 1.09 (0.387-1.79), = 0.0024), BMI (OR 6.45 (4.48-8.42), = 1.38e-10) and protein intake (OR 2.94 (0.361-5.52), = 0.026). Effects were consistent across sensitivity analyses using median-based MR methods. & , and potentially & are genetic loci identified to mediate these causal effects.

Conclusion

Our results illustrate that lifetime exposure to certain lifestyle factors has causal effects on osteoarthritis. Further studies are required to determine the efficacy of lifestyle-based interventions in reducing the population-wide disease burden of osteoarthritis.

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2025-01-15
2025-05-11

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References

  1. Disease GBD Injury I Prevalence C. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the global burden of disease study 2017. Lancet 2018 392 10159 1789 1858 10.1016/S0140‑6736(18)32279‑7 30496104
    [Google Scholar]
  2. Wallace I.J. Worthington S. Felson D.T. Jurmain R.D. Wren K.T. Maijanen H. Woods R.J. Lieberman D.E. Knee osteoarthritis has doubled in prevalence since the mid-20th century. Proc. Natl. Acad. Sci. 2017 114 35 9332 9336 10.1073/pnas.1703856114 28808025
    [Google Scholar]
  3. Belluzzi E. Hadi E.H. Granzotto M. Rossato M. Ramonda R. Macchi V. Caro D.R. Vettor R. Favero M. Systemic and local adipose tissue in knee osteoarthritis. J. Cell. Physiol. 2017 232 8 1971 1978 10.1002/jcp.25716 27925193
    [Google Scholar]
  4. Batushansky A. Zhu S. Komaravolu R.K. South S. D’souza M.P. Griffin T.M. Fundamentals of OA. An initiative of Osteoarthritis and Cartilage. Obesity and metabolic factors in OA. Osteoar. Cartil. 2022 30 4 501 515 10.1016/j.joca.2021.06.013 34537381
    [Google Scholar]
  5. Snoeker B. Turkiewicz A. Magnusson K. Frobell R. Yu D. Peat G. Englund M. Risk of knee osteoarthritis after different types of knee injuries in young adults: A population-based cohort study. Br. J. Sports Med. 2020 54 12 725 730 10.1136/bjsports‑2019‑100959 31826861
    [Google Scholar]
  6. Srikanth V.K. Fryer J.L. Zhai G. Winzenberg T.M. Hosmer D. Jones G. A meta-analysis of sex differences prevalence, incidence and severity of osteoarthritis. Osteoar. Cartil. 2005 13 9 769 781 10.1016/j.joca.2005.04.014 15978850
    [Google Scholar]
  7. Muthuri S.G. Zhang W. Maciewicz R.A. Muir K. Doherty M. Beer and wine consumption and risk of knee or hip osteoarthritis: A case control study. Arthritis Res. Ther. 2015 17 1 23 10.1186/s13075‑015‑0534‑4 25652201
    [Google Scholar]
  8. Pickering M.E. Chapurlat R. Kocher L. Derex P.L. Sleep disturbances and osteoarthritis. Pain Pract. 2016 16 2 237 244 10.1111/papr.12271 25639339
    [Google Scholar]
  9. Smith D.G. Holmes M.V. Davies N.M. Ebrahim S. Mendel’s laws, Mendelian randomization and causal inference in observational data: Substantive and nomenclatural issues. Eur. J. Epidemiol. 2020 35 2 99 111 10.1007/s10654‑020‑00622‑7 32207040
    [Google Scholar]
  10. Lee Y.H. Causal association between smoking behavior and the decreased risk of osteoarthritis: A Mendelian randomization. Z. Rheumatol. 2019 78 5 461 466 10.1007/s00393‑018‑0505‑7 29974223
    [Google Scholar]
  11. Gill D. Karhunen V. Malik R. Dichgans M. Sofat N. Cardiometabolic traits mediating the effect of education on osteoarthritis risk: A Mendelian randomization study. Osteoarthritis Cartilage 2021 29 3 365 371 10.1016/j.joca.2020.12.015 33422704
    [Google Scholar]
  12. Linnér K.R. Biroli P. Kong E. Meddens S.F.W. Wedow R. Fontana M.A. Lebreton M. Tino S.P. Abdellaoui A. Hammerschlag A.R. Nivard M.G. Okbay A. Rietveld C.A. Timshel P.N. Trzaskowski M. Vlaming R. Zünd C.L. Bao Y. Buzdugan L. Caplin A.H. Chen C.Y. Eibich P. Fontanillas P. Gonzalez J.R. Joshi P.K. Karhunen V. Kleinman A. Levin R.Z. Lill C.M. Meddens G.A. Muntané G. Roige S.S. Rooij F.J. Taskesen E. Wu Y. Zhang F. Auton A. Boardman J.D. Clark D.W. Conlin A. Dolan C.C. Fischbacher U. Groenen P.J.F. Harris K.M. Hasler G. Hofman A. Ikram M.A. Jain S. Karlsson R. Kessler R.C. Kooyman M. MacKillop J. Männikkö M. Suarez M.C. McQueen M.B. Schmidt K.M. Smart M.C. Sutter M. Thurik A.R. Uitterlinden A.G. White J. Wit H. Yang J. Bertram L. Boomsma D.I. Esko T. Fehr E. Hinds D.A. Johannesson M. Kumari M. Laibson D. Magnusson P.K.E. Meyer M.N. Navarro A. Palmer A.A. Pers T.H. Posthuma D. Schunk D. Stein M.B. Svento R. Tiemeier H. Timmers P.R.H.J. Turley P. Ursano R.J. Wagner G.G. Wilson J.F. Gratten J. Lee J.J. Cesarini D. Benjamin D.J. Koellinger P.D. Beauchamp J.P. Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences. Nat. Genet. 2019 51 2 245 257 10.1038/s41588‑018‑0309‑3 30643258
    [Google Scholar]
  13. Doherty A. Byrne S.K. Ferreira T. Holmes M.V. Holmes C. Pulit S.L. Lindgren C.M. GWAS identifies 14 loci for device-measured physical activity and sleep duration. Nat. Commun. 2018 9 1 5257 10.1038/s41467‑018‑07743‑4 30531941
    [Google Scholar]
  14. Bradbury K.E. Guo W. Cairns B.J. Armstrong M. e.g. Key T.J. Association between physical activity and body fat percentage, with adjustment for BMI: A large cross-sectional analysis of UK Biobank. BMJ Open 2017 7 3 e011843 10.1136/bmjopen‑2016‑011843 28341684
    [Google Scholar]
  15. Meddens S.F.W. de Vlaming R. Bowers P. Burik C.A.P. Linnér R.K. Lee C. Okbay A. Turley P. Rietveld C.A. Fontana M.A. Ghanbari M. Imamura F. McMahon G. van der Most P.J. Voortman T. Wade K.H. Anderson E.L. Braun K.V.E. Emmett P.M. Esko T. Gonzalez J.R. Jong K.J.C. Langenberg C. Luan J. Muka T. Ring S. Rivadeneira F. Snieder H. van Rooij F.J.A. Wolffenbuttel B.H.R. Smith G.D. Franco O.H. Forouhi N.G. Ikram M.A. Uitterlinden A.G. Ostaptchouk V.J.V. Wareham N.J. Cesarini D. Harden K.P. Lee J.J. Benjamin D.J. Chow C.C. Koellinger P.D. Genomic analysis of diet composition finds novel loci and associations with health and lifestyle. Mol. Psychiatry 2021 26 6 2056 2069 10.1038/s41380‑020‑0697‑5 32393786
    [Google Scholar]
  16. Hammerschlag A.R. Stringer S. de Leeuw C.A. Sniekers S. Taskesen E. Watanabe K. Blanken T.F. Dekker K. te Lindert B.H.W. Wassing R. Jonsdottir I. Thorleifsson G. Stefansson H. Gislason T. Berger K. Schormair B. Wellmann J. Winkelmann J. Stefansson K. Oexle K. Van Someren E.J.W. Posthuma D. Genome-wide association analysis of insomnia complaints identifies risk genes and genetic overlap with psychiatric and metabolic traits. Nat. Genet. 2017 49 11 1584 1592 10.1038/ng.3888 28604731
    [Google Scholar]
  17. Zengini E. Hatzikotoulas K. Tachmazidou I. Steinberg J. Hartwig F.P. Southam L. Hackinger S. Boer C.G. Styrkarsdottir U. Gilly A. Suveges D. Killian B. Ingvarsson T. Jonsson H. Babis G.C. McCaskie A. Uitterlinden A.G. van Meurs J.B.J. Thorsteinsdottir U. Stefansson K. Smith D.G. Wilkinson J.M. Zeggini E. Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis. Nat. Genet. 2018 50 4 549 558 10.1038/s41588‑018‑0079‑y 29559693
    [Google Scholar]
  18. Skrivankova V.W. Richmond R.C. Woolf B.A.R. Yarmolinsky J. Davies N.M. Swanson S.A. VanderWeele T.J. Higgins J.P.T. Timpson N.J. Dimou N. Langenberg C. Golub R.M. Loder E.W. Gallo V. Hansen T.A. Smith D.G. Egger M. Richards J.B. Strengthening the reporting of observational studies in epidemiology using mendelian randomization. JAMA 2021 326 16 1614 1621 10.1001/jama.2021.18236 34698778
    [Google Scholar]
  19. Davies N.M. Holmes M.V. Smith D.G. Reading Mendelian randomisation studies: A guide, glossary, and checklist for clinicians. BMJ 2018 362 k601 10.1136/bmj.k601 30002074
    [Google Scholar]
  20. Bowden J. Smith D.G. Burgess S. Mendelian randomization with invalid instruments: Effect estimation and bias detection through egger regression. Int. J. Epidemiol. 2015 44 2 512 525 10.1093/ije/dyv080 26050253
    [Google Scholar]
  21. Ho J. Mak C. Sharma V. To K. Khan W. Mendelian randomization studies of lifestyle-related risk factors for osteoarthritis: A PRISMA review and meta-analysis. Int. J. Mol. Sci. 2022 23 19 11906 10.3390/ijms231911906 36233208
    [Google Scholar]
  22. Liu M. Jiang Y. Wedow R. Li Y. Brazel D.M. Chen F. Datta G. Velderrain D.J. McGuire D. Tian C. Zhan X. Choquet H. Docherty A.R. Faul J.D. Foerster J.R. Fritsche L.G. Gabrielsen M.E. Gordon S.D. Haessler J. Hottenga J.J. Huang H. Jang S.K. Jansen P.R. Ling Y. Mägi R. Matoba N. McMahon G. Mulas A. Orrù V. Palviainen T. Pandit A. Reginsson G.W. Skogholt A.H. Smith J.A. Taylor A.E. Turman C. Willemsen G. Young H. Young K.A. Zajac G.J.M. Zhao W. Zhou W. Bjornsdottir G. Boardman J.D. Boehnke M. Boomsma D.I. Chen C. Cucca F. Davies G.E. Eaton C.B. Ehringer M.A. Esko T. Fiorillo E. Gillespie N.A. Gudbjartsson D.F. Haller T. Harris K.M. Heath A.C. Hewitt J.K. Hickie I.B. Hokanson J.E. Hopfer C.J. Hunter D.J. Iacono W.G. Johnson E.O. Kamatani Y. Kardia S.L.R. Keller M.C. Kellis M. Kooperberg C. Kraft P. Krauter K.S. Laakso M. Lind P.A. Loukola A. Lutz S.M. Madden P.A.F. Martin N.G. McGue M. McQueen M.B. Medland S.E. Metspalu A. Mohlke K.L. Nielsen J.B. Okada Y. Peters U. Polderman T.J.C. Posthuma D. Reiner A.P. Rice J.P. Rimm E. Rose R.J. Runarsdottir V. Stallings M.C. Stančáková A. Stefansson H. Thai K.K. Tindle H.A. Tyrfingsson T. Wall T.L. Weir D.R. Weisner C. Whitfield J.B. Winsvold B.S. Yin J. Zuccolo L. Bierut L.J. Hveem K. Lee J.J. Munafò M.R. Saccone N.L. Willer C.J. Cornelis M.C. David S.P. Hinds D.A. Jorgenson E. Kaprio J. Stitzel J.A. Stefansson K. Thorgeirsson T.E. Abecasis G. Liu D.J. Vrieze S. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat. Genet. 2019 51 2 237 244 10.1038/s41588‑018‑0307‑5 30643251
    [Google Scholar]
  23. Kichaev G. Bhatia G. Loh P.R. Gazal S. Burch K. Freund M.K. Schoech A. Pasaniuc B. Price A.L. Leveraging polygenic functional enrichment to improve GWAS power. Am. J. Hum. Genet. 2019 104 1 65 75 10.1016/j.ajhg.2018.11.008 30595370
    [Google Scholar]
  24. Oh Y. Chung K.C. Zinc finger protein 131 inhibits estrogen signaling by suppressing estrogen receptor α homo-dimerization. Biochem. Biophys. Res. Commun. 2013 430 1 400 405 10.1016/j.bbrc.2012.11.031 23159625
    [Google Scholar]
  25. Son Y.O. Park S. Kwak J.S. Won Y. Choi W.S. Rhee J. Chun C.H. Ryu J.H. Kim D.K. Choi H.S. Chun J.S. Estrogen-related receptor γ causes osteoarthritis by upregulating extracellular matrix-degrading enzymes. Nat. Commun. 2017 8 1 2133 10.1038/s41467‑017‑01868‑8 29247173
    [Google Scholar]
  26. Williams J.A.E. Jones C.M. Lowe M.C. Goff M.V. Francis A. Brewer G. Marian I. Morris S.L. Warwick D. Eldridge L. Julier P. Gulati M. Barker K.L. Barber V.S. Black J. Woollacott S. Young M.C. Glover V. Lamb S.E. Vincent T.L. Vincent K. Dutton S.J. Watt F.E. Hormone replacement therapy (conjugated oestrogens plus bazedoxifene) for post-menopausal women with symptomatic hand osteoarthritis: Primary report from the HOPE-e randomised, placebo-controlled, feasibility study. Lancet Rheumatol. 2022 4 10 e725 e737 10.1016/S2665‑9913(22)00218‑1 36341025
    [Google Scholar]
  27. Ijiri K. Zerbini L.F. Peng H. Otu H.H. Tsuchimochi K. Otero M. Dragomir C. Walsh N. Bierbaum B.E. Mattingly D. van Flandern G. Komiya S. Aigner T. Libermann T.A. Goldring M.B. Differential expression of GADD45β in normal and osteoarthritic cartilage: Potential role in homeostasis of articular chondrocytes. Arthritis Rheum. 2008 58 7 2075 2087 10.1002/art.23504 18576389
    [Google Scholar]
  28. Yuan H.H.S. Katyal S. Anderson J.E. A mechanism for semaphorin-induced apoptosis: DNA damage of endothelial and myogenic cells in primary cultures from skeletal muscle. Oncotarget 2018 9 32 22618 22630 10.18632/oncotarget.25200 29854302
    [Google Scholar]
  29. Weidler C. Holzer C. Harbuz M. Hofbauer R. Angele P. Schölmerich J. Straub R.H. Low density of sympathetic nerve fibres and increased density of brain derived neurotrophic factor positive cells in RA synovium. Ann. Rheum. Dis. 2005 64 1 13 20 10.1136/ard.2003.016154 15608299
    [Google Scholar]
  30. Kunath J. Delaroque N. Szardenings M. Neundorf I. Straub R.H. Sympathetic nerve repulsion inhibited by designer molecules in vitro and role in experimental arthritis. Life Sci. 2017 168 47 53 10.1016/j.lfs.2016.11.009 27856318
    [Google Scholar]
  31. Mulugeta A Eshetie TC Kassie GM Association between metabolically different adiposity subtypes and osteoarthritis: A Mendelian randomization study. Arthritis Care Res 2023 75 4 885 892
    [Google Scholar]
  32. Sun H. Zhang J. Ma Y. Liu J. Integrative genomics analysis identifies five promising genes implicated in insomnia risk based on multiple omics datasets. Biosci. Rep. 2020 40 9 BSR20201084 10.1042/BSR20201084 32830860
    [Google Scholar]
  33. Parker E. Hofer I.M.J. Rice S.J. Earl L. Anjum S.A. Deehan D.J. Loughlin J. Multi-tissue epigenetic and gene expression analysis combined with epigenome modulation identifies RWDD2B as a target of osteoarthritis susceptibility. Arthritis Rheumatol. 2021 73 1 100 109 10.1002/art.41473 32755071
    [Google Scholar]
  34. Qiu P. Jiang J. Liu Z. Cai Y. Huang T. Wang Y. Liu Q. Nie Y. Liu F. Cheng J. Li Q. Tang Y.C. Poo M. Sun Q. Chang H.C. BMAL1 knockout macaque monkeys display reduced sleep and psychiatric disorders. Natl. Sci. Rev. 2019 6 1 87 100 10.1093/nsr/nwz002 34691834
    [Google Scholar]
  35. Dudek M. Gossan N. Yang N. Im H.J. Ruckshanthi J.P.D. Yoshitane H. Li X. Jin D. Wang P. Boudiffa M. Bellantuono I. Fukada Y. Handford B.R.P. Meng Q.J. The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity. J. Clin. Invest. 2015 126 1 365 376 10.1172/JCI82755 26657859
    [Google Scholar]
  36. Chaugule S. Kim J.M. Yang Y.S. Knobeloch K.P. He X. Shim J.H. Deubiquitinating enzyme USP8 is essential for skeletogenesis by regulating WNT signaling. Int. J. Mol. Sci. 2021 22 19 10289 10.3390/ijms221910289 34638628
    [Google Scholar]
  37. Rodríguez M.C. Song M. Anta B. Calvo G.F.J. Deogracias R. Jing D. Lee F.S. Arevalo J.C. TrkB deubiquitylation by USP8 regulates receptor levels and BDNF-dependent neuronal differentiation. J. Cell Sci. 2020 133 24 jcs247841 10.1242/jcs.247841 33288548
    [Google Scholar]
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The Causal Effects of Lifestyle Factors on Osteoarthritis: A Two-sample Mendelian Randomisation Study
Bentham Science Publishers ; https://doi.org/10.2174/0115733971335445241203054553
/content/journals/crr/10.2174/0115733971335445241203054553
/content/journals/crr/10.2174/0115733971335445241203054553
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  • Article Type:     Research Article
Keywords: diet 6 ; lifestyle factors 2 ; Osteoarthritis 1 ; insomnia 5 ; mendelian randomization 3 ; BMI 4

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