Skip to main content
Top
Published in: Journal of Orthopaedic Surgery and Research 1/2024

Open Access 01-12-2024 | Shoulder Stiffness | Research article

Bidirectional two-sample Mendelian randomization analysis identifies causal associations between cardiovascular diseases and frozen shoulder

Authors: WeiSong Lu, Bin Pu, Sen Wang, MengZe Li, Yue An, Jie Lian, YongQuan Wang

Published in: Journal of Orthopaedic Surgery and Research | Issue 1/2024

Login to get access

Abstract

Background

Although prior observational studies indicate an association between cardiovascular diseases (CVDs) and frozen shoulder (FS), the potential causal relationship between them remains uncertain. This study aims to explore the genetic causal relationship between CVDs and FS using Mendelian randomization (MR).

Methods

Genetic variations closely associated with FS were obtained from the FinnGen Consortium. Summary data for CVD, including atrial fibrillation (AF), coronary artery disease (CAD), heart failure (HF), myocardial infarction (MI), stroke, and ischemic stroke (IS), were sourced from several large-scale genome-wide association studies (GWAS). MR analysis was performed using inverse variance weighting (IVW), MR Egger, and weighted median methods. IVW, as the primary MR analysis method, complemented by other sensitivity analyses, was utilized to validate the robustness of the results. Further reverse MR analysis was conducted to explore the presence of reverse causal relationships.

Results

In the forward MR analysis, genetically determined risk of stroke and IS was positively associated with FS (OR [95% CI] = 1.58 (1.23–2.03), P < 0.01; OR [95% CI] = 1.46 (1.16–1.85), P < 0.01, respectively). There was no strong evidence of an effect of genetically predicted other CVDs on FS risk. Sensitivity analyses confirmed the robustness of the results. In the reverse MR analysis, no causal relationships were observed between FS and various CVDs.

Conclusion

The study suggests that stroke increases the risk of developing FS. However, further basic and clinical research is needed to substantiate our findings.
Appendix
Available only for authorised users
Literature
2.
go back to reference Kim DH, Kim YS, Kim BS, Sung DH, Song KS, Cho CH. Is frozen shoulder completely resolved at 2 years after the onset of disease? J Orthop Sci. 2020;25(2):224–8.PubMedCrossRef Kim DH, Kim YS, Kim BS, Sung DH, Song KS, Cho CH. Is frozen shoulder completely resolved at 2 years after the onset of disease? J Orthop Sci. 2020;25(2):224–8.PubMedCrossRef
3.
go back to reference Hand C, Clipsham K, Rees JL, Carr AJ. Long-term outcome of frozen shoulder. J Shoulder Elbow Surg. 2008;17(2):231–6.PubMedCrossRef Hand C, Clipsham K, Rees JL, Carr AJ. Long-term outcome of frozen shoulder. J Shoulder Elbow Surg. 2008;17(2):231–6.PubMedCrossRef
4.
go back to reference Date A, Rahman L. Frozen shoulder: overview of clinical presentation and review of the current evidence base for management strategies. Future Sci OA. 2020;6(10):FSO647.PubMedPubMedCentralCrossRef Date A, Rahman L. Frozen shoulder: overview of clinical presentation and review of the current evidence base for management strategies. Future Sci OA. 2020;6(10):FSO647.PubMedPubMedCentralCrossRef
5.
go back to reference Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, Himmelfarb CD, Khera A, Lloyd-Jones D, McEvoy JW, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice guidelines. Circulation. 2019;140(11):e596–646.PubMedPubMedCentral Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, Himmelfarb CD, Khera A, Lloyd-Jones D, McEvoy JW, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice guidelines. Circulation. 2019;140(11):e596–646.PubMedPubMedCentral
6.
go back to reference Collaborators GBDCoD: Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018, 392(10159):1736–1788. Collaborators GBDCoD: Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018, 392(10159):1736–1788.
7.
go back to reference Tie K, Wang H, Yang X, Ni Q, Chen L. Analysis of risk factors for advanced age in patients with frozen shoulder. Aging Clin Exp Res. 2023;35(3):615–20.PubMed Tie K, Wang H, Yang X, Ni Q, Chen L. Analysis of risk factors for advanced age in patients with frozen shoulder. Aging Clin Exp Res. 2023;35(3):615–20.PubMed
8.
go back to reference Kang JH, Sheu JJ, Lin HC. Increased risk of stroke after adhesive capsulitis: a population-based study. Stroke. 2010;41(5):1044–7.PubMedCrossRef Kang JH, Sheu JJ, Lin HC. Increased risk of stroke after adhesive capsulitis: a population-based study. Stroke. 2010;41(5):1044–7.PubMedCrossRef
9.
go back to reference Kang JH, Keller JJ, Lin HC. A population-based follow-up study on the risk of acute myocardial infarction following adhesive capsulitis. Int J Cardiol. 2012;157(2):289–91.PubMedCrossRef Kang JH, Keller JJ, Lin HC. A population-based follow-up study on the risk of acute myocardial infarction following adhesive capsulitis. Int J Cardiol. 2012;157(2):289–91.PubMedCrossRef
10.
11.
go back to reference Sekula P, Del Greco MF, Pattaro C, Kottgen A. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol. 2016;27(11):3253–65.PubMedPubMedCentralCrossRef Sekula P, Del Greco MF, Pattaro C, Kottgen A. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol. 2016;27(11):3253–65.PubMedPubMedCentralCrossRef
12.
go back to reference Burgess S, Small DS, Thompson SG. A review of instrumental variable estimators for Mendelian randomization. Stat Methods Med Res. 2017;26(5):2333–55.MathSciNetPubMedCrossRef Burgess S, Small DS, Thompson SG. A review of instrumental variable estimators for Mendelian randomization. Stat Methods Med Res. 2017;26(5):2333–55.MathSciNetPubMedCrossRef
13.
go back to reference Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey Smith G. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med. 2008;27(8):1133–63.MathSciNetPubMedCrossRef Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey Smith G. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med. 2008;27(8):1133–63.MathSciNetPubMedCrossRef
14.
go back to reference Lv X, Hu Z, Liang F, Liu S, Gong H, Du J, Deng X, Qian JH, Nie Q, Luo J. Causal relationship between ischemic stroke and its subtypes and frozen shoulder: a two-sample Mendelian randomization analysis. Front Neurol. 2023;14:1178051.PubMedPubMedCentralCrossRef Lv X, Hu Z, Liang F, Liu S, Gong H, Du J, Deng X, Qian JH, Nie Q, Luo J. Causal relationship between ischemic stroke and its subtypes and frozen shoulder: a two-sample Mendelian randomization analysis. Front Neurol. 2023;14:1178051.PubMedPubMedCentralCrossRef
15.
go back to reference Nielsen JB, Thorolfsdottir RB, Fritsche LG, Zhou W, Skov MW, Graham SE, Herron TJ, McCarthy S, Schmidt EM, Sveinbjornsson G, et al. Biobank-driven genomic discovery yields new insight into atrial fibrillation biology. Nat Genet. 2018;50(9):1234–9.PubMedPubMedCentralCrossRef Nielsen JB, Thorolfsdottir RB, Fritsche LG, Zhou W, Skov MW, Graham SE, Herron TJ, McCarthy S, Schmidt EM, Sveinbjornsson G, et al. Biobank-driven genomic discovery yields new insight into atrial fibrillation biology. Nat Genet. 2018;50(9):1234–9.PubMedPubMedCentralCrossRef
16.
go back to reference van der Harst P, Verweij N. Identification of 64 novel genetic loci provides an expanded view on the genetic architecture of coronary artery disease. Circ Res. 2018;122(3):433–43.PubMedPubMedCentralCrossRef van der Harst P, Verweij N. Identification of 64 novel genetic loci provides an expanded view on the genetic architecture of coronary artery disease. Circ Res. 2018;122(3):433–43.PubMedPubMedCentralCrossRef
17.
go back to reference Shah S, Henry A, Roselli C, Lin H, Sveinbjornsson G, Fatemifar G, Hedman AK, Wilk JB, Morley MP, Chaffin MD, et al. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure. Nat Commun. 2020;11(1):163.ADSPubMedPubMedCentralCrossRef Shah S, Henry A, Roselli C, Lin H, Sveinbjornsson G, Fatemifar G, Hedman AK, Wilk JB, Morley MP, Chaffin MD, et al. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure. Nat Commun. 2020;11(1):163.ADSPubMedPubMedCentralCrossRef
18.
go back to reference Hartiala JA, Han Y, Jia Q, Hilser JR, Huang P, Gukasyan J, Schwartzman WS, Cai Z, Biswas S, Tregouet DA, et al. Genome-wide analysis identifies novel susceptibility loci for myocardial infarction. Eur Heart J. 2021;42(9):919–33.PubMedPubMedCentralCrossRef Hartiala JA, Han Y, Jia Q, Hilser JR, Huang P, Gukasyan J, Schwartzman WS, Cai Z, Biswas S, Tregouet DA, et al. Genome-wide analysis identifies novel susceptibility loci for myocardial infarction. Eur Heart J. 2021;42(9):919–33.PubMedPubMedCentralCrossRef
19.
go back to reference Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, et al. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet. 2018;50(4):524–37.PubMedPubMedCentralCrossRef Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, et al. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet. 2018;50(4):524–37.PubMedPubMedCentralCrossRef
20.
go back to reference Burgess S, Thompson SG, Collaboration CCG. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol. 2011;40(3):755–64.PubMedCrossRef Burgess S, Thompson SG, Collaboration CCG. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol. 2011;40(3):755–64.PubMedCrossRef
21.
go back to reference Zhang Y, Xiong Y, Shen S, Yang J, Wang W, Wu T, Chen L, Yu Q, Zuo H, Wang X, et al. Causal association between tea consumption and kidney function: a Mendelian randomization study. Front Nutr. 2022;9: 801591.PubMedPubMedCentralCrossRef Zhang Y, Xiong Y, Shen S, Yang J, Wang W, Wu T, Chen L, Yu Q, Zuo H, Wang X, et al. Causal association between tea consumption and kidney function: a Mendelian randomization study. Front Nutr. 2022;9: 801591.PubMedPubMedCentralCrossRef
22.
go back to reference Shim H, Chasman DI, Smith JD, Mora S, Ridker PM, Nickerson DA, Krauss RM, Stephens M. 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.PubMedPubMedCentralCrossRef Shim H, Chasman DI, Smith JD, Mora S, Ridker PM, Nickerson DA, Krauss RM, Stephens M. 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.PubMedPubMedCentralCrossRef
23.
go back to reference Borenstein M, Hedges LV, Higgins JP, Rothstein HR. A basic introduction to fixed-effect and random-effects models for meta-analysis. Res Synth Methods. 2010;1(2):97–111.PubMedCrossRef Borenstein M, Hedges LV, Higgins JP, Rothstein HR. A basic introduction to fixed-effect and random-effects models for meta-analysis. Res Synth Methods. 2010;1(2):97–111.PubMedCrossRef
24.
go back to reference Bowden J, Del Greco MF, Minelli C, Zhao Q, Lawlor DA, Sheehan NA, Thompson J, Davey Smith G. Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption. Int J Epidemiol. 2019;48(3):728–42.PubMedCrossRef Bowden J, Del Greco MF, Minelli C, Zhao Q, Lawlor DA, Sheehan NA, Thompson J, Davey Smith G. Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption. Int J Epidemiol. 2019;48(3):728–42.PubMedCrossRef
25.
go back to reference Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50(5):693–8.PubMedPubMedCentralCrossRef Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50(5):693–8.PubMedPubMedCentralCrossRef
26.
go back to reference 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):1985–98.PubMedPubMedCentralCrossRef 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):1985–98.PubMedPubMedCentralCrossRef
27.
go back to reference Dong Q, Chen D, Zhang Y, Xu Y, Yan L, Jiang J. Constipation and cardiovascular disease: a two-sample Mendelian randomization analysis. Front Cardiovasc Med. 2023;10:1080982.PubMedPubMedCentralCrossRef Dong Q, Chen D, Zhang Y, Xu Y, Yan L, Jiang J. Constipation and cardiovascular disease: a two-sample Mendelian randomization analysis. Front Cardiovasc Med. 2023;10:1080982.PubMedPubMedCentralCrossRef
28.
go back to reference Wang Q, Hu S, Qi L, Wang X, Jin G, Wu D, Wang Y, Ren L. Causal associations between sleep traits and brain structure: a bidirectional Mendelian randomization study. Behav Brain Funct. 2023;19(1):17.PubMedPubMedCentralCrossRef Wang Q, Hu S, Qi L, Wang X, Jin G, Wu D, Wang Y, Ren L. Causal associations between sleep traits and brain structure: a bidirectional Mendelian randomization study. Behav Brain Funct. 2023;19(1):17.PubMedPubMedCentralCrossRef
29.
go back to reference Skrivankova VW, Richmond RC, Woolf BAR, Yarmolinsky J, Davies NM, Swanson SA, VanderWeele TJ, Higgins JPT, Timpson NJ, Dimou N, et al. Strengthening the reporting of observational studies in epidemiology using mendelian randomization: the STROBE-MR statement. JAMA. 2021;326(16):1614–21.PubMedCrossRef Skrivankova VW, Richmond RC, Woolf BAR, Yarmolinsky J, Davies NM, Swanson SA, VanderWeele TJ, Higgins JPT, Timpson NJ, Dimou N, et al. Strengthening the reporting of observational studies in epidemiology using mendelian randomization: the STROBE-MR statement. JAMA. 2021;326(16):1614–21.PubMedCrossRef
30.
go back to reference Pinedo S, de la Villa FM. Complications in the hemiplegic patient in the first year after the stroke. Rev Neurol. 2001;32(3):206–9.PubMed Pinedo S, de la Villa FM. Complications in the hemiplegic patient in the first year after the stroke. Rev Neurol. 2001;32(3):206–9.PubMed
31.
go back to reference Lo SF, Chen SY, Lin HC, Jim YF, Meng NH, Kao MJ. Arthrographic and clinical findings in patients with hemiplegic shoulder pain. Arch Phys Med Rehabil. 2003;84(12):1786–91.PubMedCrossRef Lo SF, Chen SY, Lin HC, Jim YF, Meng NH, Kao MJ. Arthrographic and clinical findings in patients with hemiplegic shoulder pain. Arch Phys Med Rehabil. 2003;84(12):1786–91.PubMedCrossRef
32.
go back to reference Suethanapornkul S, Kuptniratsaikul PS, Kuptniratsaikul V, Uthensut P, Dajpratha P, Wongwisethkarn J. Post stroke shoulder subluxation and shoulder pain: a cohort multicenter study. J Med Assoc Thai. 2008;91(12):1885–92.PubMed Suethanapornkul S, Kuptniratsaikul PS, Kuptniratsaikul V, Uthensut P, Dajpratha P, Wongwisethkarn J. Post stroke shoulder subluxation and shoulder pain: a cohort multicenter study. J Med Assoc Thai. 2008;91(12):1885–92.PubMed
34.
go back to reference Zeng J, Bao T, Yang K, Zhu X, Wang S, Xiang W, Ge A, Zeng L, Ge J. The mechanism of microglia-mediated immune inflammation in ischemic stroke and the role of natural botanical components in regulating microglia: a review. Front Immunol. 2022;13:1047550.PubMedCrossRef Zeng J, Bao T, Yang K, Zhu X, Wang S, Xiang W, Ge A, Zeng L, Ge J. The mechanism of microglia-mediated immune inflammation in ischemic stroke and the role of natural botanical components in regulating microglia: a review. Front Immunol. 2022;13:1047550.PubMedCrossRef
35.
go back to reference Lho YM, Ha E, Cho CH, Song KS, Min BW, Bae KC, Lee KJ, Hwang I, Park HB. Inflammatory cytokines are overexpressed in the subacromial bursa of frozen shoulder. J Shoulder Elbow Surg. 2013;22(5):666–72.PubMedCrossRef Lho YM, Ha E, Cho CH, Song KS, Min BW, Bae KC, Lee KJ, Hwang I, Park HB. Inflammatory cytokines are overexpressed in the subacromial bursa of frozen shoulder. J Shoulder Elbow Surg. 2013;22(5):666–72.PubMedCrossRef
36.
go back to reference Hand GC, Athanasou NA, Matthews T, Carr AJ. The pathology of frozen shoulder. J Bone Joint Surg Br. 2007;89(7):928–32.PubMedCrossRef Hand GC, Athanasou NA, Matthews T, Carr AJ. The pathology of frozen shoulder. J Bone Joint Surg Br. 2007;89(7):928–32.PubMedCrossRef
37.
go back to reference de Oliveira RA, de Andrade DC, Machado AG, Teixeira MJ. Central poststroke pain: somatosensory abnormalities and the presence of associated myofascial pain syndrome. BMC Neurol. 2012;12:89.PubMedPubMedCentralCrossRef de Oliveira RA, de Andrade DC, Machado AG, Teixeira MJ. Central poststroke pain: somatosensory abnormalities and the presence of associated myofascial pain syndrome. BMC Neurol. 2012;12:89.PubMedPubMedCentralCrossRef
38.
39.
go back to reference Winter Y, Uphaus T, Sandner K, Klimpe S, Stuckrad-Barre SV, Groppa S. Efficacy and safety of antiseizure medication in post-stroke epilepsy. Seizure. 2022;100:109–14.PubMedCrossRef Winter Y, Uphaus T, Sandner K, Klimpe S, Stuckrad-Barre SV, Groppa S. Efficacy and safety of antiseizure medication in post-stroke epilepsy. Seizure. 2022;100:109–14.PubMedCrossRef
40.
go back to reference Kilkenny MF, Olaiya MT, Dalli LL, Kim J, Andrew NE, Sanfilippo FM, Thrift AG, Nelson M, Pearce C, Sanders L, et al. Treatment with multiple therapeutic classes of medication is associated with survival after stroke. Neuroepidemiology. 2022;56(1):66–74.PubMedCrossRef Kilkenny MF, Olaiya MT, Dalli LL, Kim J, Andrew NE, Sanfilippo FM, Thrift AG, Nelson M, Pearce C, Sanders L, et al. Treatment with multiple therapeutic classes of medication is associated with survival after stroke. Neuroepidemiology. 2022;56(1):66–74.PubMedCrossRef
41.
go back to reference Wu CH, Wang YH, Huang YP, Pan SL. Does adhesive capsulitis of the shoulder increase the risk of stroke? A population-based propensity score-matched follow-up study. PLoS ONE. 2012;7(11): e49343.ADSPubMedPubMedCentralCrossRef Wu CH, Wang YH, Huang YP, Pan SL. Does adhesive capsulitis of the shoulder increase the risk of stroke? A population-based propensity score-matched follow-up study. PLoS ONE. 2012;7(11): e49343.ADSPubMedPubMedCentralCrossRef
43.
go back to reference Bulgen DY, Binder A, Hazleman BL, Park JR. Immunological studies in frozen shoulder. J Rheumatol. 1982;9(6):893–8.PubMed Bulgen DY, Binder A, Hazleman BL, Park JR. Immunological studies in frozen shoulder. J Rheumatol. 1982;9(6):893–8.PubMed
44.
go back to reference Verma S. C-reactive protein incites atherosclerosis. Can J Cardiol. 2004;20(Suppl B):291–311. Verma S. C-reactive protein incites atherosclerosis. Can J Cardiol. 2004;20(Suppl B):291–311.
Metadata
Title
Bidirectional two-sample Mendelian randomization analysis identifies causal associations between cardiovascular diseases and frozen shoulder
Authors
WeiSong Lu
Bin Pu
Sen Wang
MengZe Li
Yue An
Jie Lian
YongQuan Wang
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Journal of Orthopaedic Surgery and Research / Issue 1/2024
Electronic ISSN: 1749-799X
DOI
https://doi.org/10.1186/s13018-024-04600-7

Other articles of this Issue 1/2024

Journal of Orthopaedic Surgery and Research 1/2024 Go to the issue