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2000
Volume 26, Issue 5
  • ISSN: 1389-2010
  • E-ISSN: 1873-4316

Abstract

Background

The relationship between uterine fibroids and keloid/hypertrophic scars has been contradictory. Our research employs a bidirectional Mendelian Randomization (MR) approach to establish a clearer understanding of this potential causal link.

Objective

This study aimed to determine the effect of uterine fibroids on keloid/hypertrophic scars and the effect of keloid/hypertrophic scars on uterine fibroids.

Purpose

We aimed to demonstrate the relationship between uterine fibroids and keloid/hypertrophic scars.

Methods

Our bidirectional MR study utilized summarized data from genome-wide association studies (GWAS) focused on European populations. Our primary tool for establishing causality was the Inverse-Variance Weighted (IVW) method. To reinforce the IVW findings, we also applied four alternative MR methods: MR-Egger, Maximum Likelihood, Weighted Mode, and Weighted Median.

Results

The IVW method indicated a significant causal link, with uterine fibroids greatly raising the likelihood of developing keloids (Odds Ratio [OR] = 1.202, 95% Confidence Interval [CI]: 1.045-1.381; P=0.010) and hypertrophic scars (OR = 1.256, 95% CI: 1.039-1.519; P=0.018). Parallel results were observed with the MR-Egger, Maximum Likelihood, Weighted Mode, and Weighted Median methods. Sensitivity analyses indicated robustness in these findings, with no evidence of heterogeneity or horizontal pleiotropy. Conversely, the reverse MR analysis did not demonstrate an increased risk of uterine fibroids due to keloids or hypertrophic scars.

Conclusion

This study elucidates a significant causal effect of uterine fibroids on the development of keloid and hypertrophic scars, offering valuable insights into their pathogenesis and potential therapeutic targets.

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References

  1. UngC.Y. WarwickA. OnoufriadisA. BarkerJ.N. ParsonsM. McGrathJ.A. ShawT.J. DandN. Comorbidities of keloid and hypertrophic scars among participants in UK biobank.JAMA Dermatol.2023159217218110.1001/jamadermatol.2022.5607 36598763
    [Google Scholar]
  2. GlassD.A.II Current understanding of the genetic causes of keloid formation.J. Investig. Dermatol. Symp. Proc.2017182S50S5310.1016/j.jisp.2016.10.024 28941494
    [Google Scholar]
  3. JonesL.R. YoungW. DivineG. DattaI. ChenK.M. OzogD. WorshamM.J. Genome-wide scan for methylation profiles in keloids.Dis. Markers201520151710.1155/2015/943176 26074660
    [Google Scholar]
  4. TéotL. MustoeT.A. MiddelkoopE. GauglitzG.G. Textbook on Scar Management: State of the Art Management and Emerging Technologies.ChamSpringer202010.1007/978‑3‑030‑44766‑3
    [Google Scholar]
  5. XueM. JacksonC.J. Extracellular matrix reorganization during wound healing and its impact on abnormal scarring.Adv. Wound Care (New Rochelle)20154311913610.1089/wound.2013.0485 25785236
    [Google Scholar]
  6. HuangC. AkaishiS. HyakusokuH. OgawaR. Are keloid and hypertrophic scar different forms of the same disorder? A fibroproliferative skin disorder hypothesis based on keloid findings.Int. Wound J.201411551752210.1111/j.1742‑481X.2012.01118.x 23173565
    [Google Scholar]
  7. MarellaP. GlassD.A. II A retrospective study on the association of keloids with underlying health conditions in African-American Women.Int. J. Womens Dermatol.202391e07410.1097/JW9.0000000000000074 36846187
    [Google Scholar]
  8. SearleT. AliF.R. Al-NiaimiF. The role of pharmacogenetics in keloid scar treatment: A literature review.Scars. Burn. Heal.2020610.1177/2059513120941704 32922964
    [Google Scholar]
  9. LiuR. XiaoH. WangR. LiW. DengK. CenY. XuX. Risk factors associated with the progression from keloids to severe keloids.Chin. Med. J. (Engl.)2022135782883610.1097/CM9.0000000000002093 35288506
    [Google Scholar]
  10. BayatA. ArscottG. OllierW.E.R. Mc GroutherD.A. FergusonM.W.J. Keloid disease: clinical relevance of single versus multiple site scars.Br. J. Plast. Surg.2005581283710.1016/j.bjps.2004.04.024 15629164
    [Google Scholar]
  11. SunL.M. WangK.H. LeeY.C.G. Keloid incidence in Asian people and its comorbidity with other fibrosis-related diseases: A nationwide population-based study.Arch. Dermatol. Res.2014306980380810.1007/s00403‑014‑1491‑5 25081927
    [Google Scholar]
  12. LuC.C. QinH. ZhangZ.H. ZhangC.L. LuY.Y. WuC.H. The association between keloid and osteoporosis: real-world evidence.BMC Musculoskelet. Disord.20212213910.1186/s12891‑020‑03898‑8 33413286
    [Google Scholar]
  13. HahnJ.M. SuppD.M. Abnormal expression of the vitamin D receptor in keloid scars.Burns20174371506151510.1016/j.burns.2017.04.009 28778755
    [Google Scholar]
  14. LeppertP.C. CatherinoW.H. SegarsJ.H. A new hypothesis about the origin of uterine fibroids based on gene expression profiling with microarrays.Am. J. Obstet. Gynecol.2006195241542010.1016/j.ajog.2005.12.059 16635466
    [Google Scholar]
  15. Day BairdD. DunsonD.B. HillM.C. CousinsD. SchectmanJ.M. High cumulative incidence of uterine leiomyoma in black and white women: Ultrasound evidence.Am. J. Obstet. Gynecol.2003188110010710.1067/mob.2003.99 12548202
    [Google Scholar]
  16. LaughlinS. SchroederJ. BairdD. New directions in the epidemiology of uterine fibroids.Semin. Reprod. Med.201028320421710.1055/s‑0030‑1251477 20414843
    [Google Scholar]
  17. MarshE.E. Al-HendyA. KappusD. GalitskyA. StewartE.A. KerolousM. Burden, prevalence, and treatment of uterine fibroids: A survey of U.S. women.J. Womens Health (Larchmt.)201827111359136710.1089/jwh.2018.7076 30230950
    [Google Scholar]
  18. CatherinoW.H. LeppertP.C. StenmarkM.H. PaysonM. Potlog-NahariC. NiemanL.K. SegarsJ.H. Reduced dermatopontin expression is a molecular link between uterine leiomyomas and keloids.Genes Chromosomes Cancer200440320421710.1002/gcc.20035 15139000
    [Google Scholar]
  19. MalikM. NorianJ. McCarthy-KeithD. BrittenJ. CatherinoW. Why leiomyomas are called fibroids: The central role of extracellular matrix in symptomatic women.Semin. Reprod. Med.201028316917910.1055/s‑0030‑1251475 20414841
    [Google Scholar]
  20. ChenW. FuX. SunX. SunT. ZhaoZ. ShengZ. Analysis of differentially expressed genes in keloids and normal skin with cDNA microarray.J. Surg. Res.2003113220821610.1016/S0022‑4804(03)00188‑4 12957131
    [Google Scholar]
  21. FlakeG.P. AndersenJ. DixonD. Etiology and pathogenesis of uterine leiomyomas: A review.Environ. Health Perspect.200311181037105410.1289/ehp.5787 12826476
    [Google Scholar]
  22. CarrinoD.A. MesianoS. BarkerN.M. HurdW.W. CaplanA.I. Proteoglycans of uterine fibroids and keloid scars: Similarity in their proteoglycan composition.Biochem. J.2012443236136810.1042/BJ20111996 22257180
    [Google Scholar]
  23. OkoloS.O. GentryC.C. PerrettC.W. MacleanA.B. Familial prevalence of uterine fibroids is associated with distinct clinical and molecular features.Hum. Reprod.20052082321232410.1093/humrep/dei049 15860490
    [Google Scholar]
  24. ShanM. LiuH. HaoY. MengT. FengC. SongK. WangY. IL-4 and CCR7 play an important role in the development of keloids in patients with a family history.Am. J. Transl. Res.202214533813394 35702126
    [Google Scholar]
  25. BothwellL.E. PodolskyS.H. The emergence of the randomized, controlled trial.N. Engl. J. Med.2016375650150410.1056/NEJMp1604635 27509097
    [Google Scholar]
  26. SwansonS.A. TiemeierH. IkramM.A. HernánM.A. Nature as a trialist?Epidemiology201728565365910.1097/EDE.0000000000000699 28590373
    [Google Scholar]
  27. SekulaP. F. Del GrecoM. PattaroC. KöttgenA. Mendelian randomization as an approach to assess causality using observational data.J. Am. Soc. Nephrol.201627113253326510.1681/ASN.2016010098 27486138
    [Google Scholar]
  28. SakaueS. KanaiM. TanigawaY. KarjalainenJ. KurkiM. KoshibaS. NaritaA. KonumaT. YamamotoK. AkiyamaM. IshigakiK. SuzukiA. SuzukiK. ObaraW. YamajiK. TakahashiK. AsaiS. TakahashiY. SuzukiT. ShinozakiN. YamaguchiH. MinamiS. MurayamaS. YoshimoriK. NagayamaS. ObataD. HigashiyamaM. MasumotoA. KoretsuneY. ItoK. TeraoC. YamauchiT. KomuroI. KadowakiT. TamiyaG. YamamotoM. NakamuraY. KuboM. MurakamiY. YamamotoK. KamataniY. PalotieA. RivasM.A. DalyM.J. MatsudaK. OkadaY. A cross-population atlas of genetic associations for 220 human phenotypes.Nat. Genet.202153101415142410.1038/s41588‑021‑00931‑x 34594039
    [Google Scholar]
  29. BurgessS. SmallD.S. ThompsonS.G. A review of instrumental variable estimators for Mendelian randomization.Stat. Methods Med. Res.20172652333235510.1177/0962280215597579 26282889
    [Google Scholar]
  30. LiuX. LiuY. JinH. KhodeiryM.M. KongW. WangN. LeeJ.K. LeeR.K. Reactive fibroblasts in response to optic nerve crush injury.Mol. Neurobiol.20215841392140310.1007/s12035‑020‑02199‑4 33184784
    [Google Scholar]
  31. LiQ. ZhongJ. YiD. DengG. LiuZ. WangW. Assessing the risk of rapid fibroid growth in patients with asymptomatic solitary uterine myoma using a multivariate prediction model.Ann. Transl. Med.20219537010.21037/atm‑20‑4559 33842591
    [Google Scholar]
  32. LimandjajaG.C. WaaijmanT. RoffelS. NiessenF.B. GibbsS. Monocytes co-cultured with reconstructed keloid and normal skin models skew towards M2 macrophage phenotype.Arch. Dermatol. Res.2019311861562710.1007/s00403‑019‑01942‑9 31187196
    [Google Scholar]
  33. KamatM.A. BlackshawJ.A. YoungR. SurendranP. BurgessS. DaneshJ. ButterworthA.S. StaleyJ.R. PhenoScanner V2: An expanded tool for searching human genotype–phenotype associations.Bioinformatics201935224851485310.1093/bioinformatics/btz469 31233103
    [Google Scholar]
  34. HemaniG. ZhengJ. ElsworthB. WadeK.H. HaberlandV. BairdD. LaurinC. BurgessS. BowdenJ. LangdonR. TanV.Y. YarmolinskyJ. ShihabH.A. TimpsonN.J. EvansD.M. ReltonC. MartinR.M. Davey SmithG. GauntT.R. HaycockP.C. The MR-Base platform supports systematic causal inference across the human phenome.eLife20187e3440810.7554/eLife.34408 29846171
    [Google Scholar]
  35. ShuM.J. LiJ.R. ZhuY.C. ShenH. Migraine and ischemic stroke: A mendelian randomization study.Neurol. Ther.202211123724610.1007/s40120‑021‑00310‑y 34904213
    [Google Scholar]
  36. YangM. LuoP. ZhangF. XuK. FengR. XuP. Large-scale correlation analysis of deep venous thrombosis and gut microbiota.Front. Cardiovasc. Med.20229102591810.3389/fcvm.2022.1025918 36419497
    [Google Scholar]
  37. LeeY.H. Causal association between smoking behavior and the decreased risk of osteoarthritis: A Mendelian randomization.Z. Rheumatol.201978546146610.1007/s00393‑018‑0505‑7 29974223
    [Google Scholar]
  38. YavorskaO.O. BurgessS. Mendelianrandomization: an r package for performing mendelian randomization analyses using summarized data.Int. J. Epidemiol.20174661734173910.1093/ije/dyx034 28398548
    [Google Scholar]
  39. VerbanckM. ChenC.Y. NealeB. DoR. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases.Nat. Genet.201850569369810.1038/s41588‑018‑0099‑7 29686387
    [Google Scholar]
  40. YanM. FuL.L. NadaO.A. ChenL.M. GosauM. SmeetsR. FengH.C. FriedrichR.E. Evaluation of the effects of human dental pulp stem cells on the biological phenotype of hypertrophic keloid fibroblasts.Cells2021107180310.3390/cells10071803 34359971
    [Google Scholar]
  41. TosaM. OgawaR. Photodynamic therapy for keloids and hypertrophic scars: a review.Scars. Burn. Heal.2020610.1177/2059513120932059 32655901
    [Google Scholar]
  42. LimandjajaG.C. NiessenF.B. ScheperR.J. GibbsS. Hypertrophic scars and keloids: Overview of the evidence and practical guide for differentiating between these abnormal scars.Exp. Dermatol.202130114616110.1111/exd.14121 32479693
    [Google Scholar]
  43. Cruz-ÁvilaH.A. VallejoM. Martínez-GarcíaM. Hernández-LemusE. Comorbidity networks in cardiovascular diseases.Front. Physiol.202011100910.3389/fphys.2020.01009 32982776
    [Google Scholar]
  44. BlobeG.C. SchiemannW.P. LodishH.F. Role of transforming growth factor beta in human disease.N. Engl. J. Med.2000342181350135810.1056/NEJM200005043421807 10793168
    [Google Scholar]
  45. LuoX. PanQ. LiuL. CheginiN. Genomic and proteomic profiling II: Comparative assessment of gene expression profiles in leiomyomas, keloids, and surgically-induced scars.Reprod. Biol. Endocrinol.2007513510.1186/1477‑7827‑5‑35 17718906
    [Google Scholar]
  46. HarmonQ.E. LaughlinS.K. BairdD.D. Keloids and ultrasound detected fibroids in young African American women.PLoS One2013812e8473710.1371/journal.pone.0084737 24386410
    [Google Scholar]
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