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Associations of muscle mass and grip strength with severe NAFLD: A prospective study of 333,295 UK Biobank participants

  • Author Footnotes
    # These authors contributed equally to the study.
    Lanlan Chen
    Footnotes
    # These authors contributed equally to the study.
    Affiliations
    Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, Jilin, China
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  • Author Footnotes
    # These authors contributed equally to the study.
    Zhongqi Fan
    Footnotes
    # These authors contributed equally to the study.
    Affiliations
    Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, Jilin, China
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  • Guoyue Lv
    Correspondence
    Corresponding author. Address: Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, Jilin, China.
    Affiliations
    Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, Jilin, China
    Search for articles by this author
  • Author Footnotes
    # These authors contributed equally to the study.

      Linked Article

      To the Editor:
      We read with great interest the study by Petermann-Rocha et al. which revealed the inverse associations of muscle mass and grip strength with the risk of developing severe non-alcoholic fatty liver disease (NAFLD) using 333,295 participants from the UK Biobank (UKBB).
      • Petermann-Rocha F.
      • Gray S.R.
      • Forrest E.
      • Welsh P.
      • Sattar N.
      • Celis-Morales C.
      • et al.
      Associations of muscle mass and grip strength with severe NAFLD: a prospective study of 333,295 UK Biobank participants.
      Although this study has adjusted for several potential confounders including age, sex, deprivation, ethnicity, smoking, drinking, the components of metabolic syndromes and physical activity, the results can hardly be interpreted as causal associations.
      Mendelian randomization (MR) design is an increasingly popular method of causal inference in epidemiology, which uses genetic variants as the instrumental variables to estimate the association between genetically predicted exposure on an outcome.
      • Emdin C.A.
      • Khera A.V.
      • Kathiresan S.
      Mendelian randomization.
      Since genetic variants are randomly allocated at conception, the MR design can be deemed as nature’s randomization and can deduce the causal relationship. Previously, we reported that genetically predicted higher levels of low-density lipoprotein cholesterol could lower the risk of cholelithiasis using a MR design.
      • Chen L.
      • Yang H.
      • Li H.
      • He C.
      • Yang L.
      • Lv G.
      Insights into modifiable risk factors of cholelithiasis: a Mendelian randomization study.
      Herein, we attempted to answer whether the associations of muscle mass and grip strength with NAFLD were causal using the MR design.
      Two sarcopenia-associated traits from the UKBB were included in this study, namely grip strength (right & left) and appendicular lean mass (ALM).
      • Pei Y.F.
      • Liu Y.Z.
      • Yang X.L.
      • Zhang H.
      • Feng G.J.
      • Wei X.T.
      • et al.
      The genetic architecture of appendicular lean mass characterized by association analysis in the UK Biobank study.
      Three genome-wide association studies (GWASs) of NAFLD without UKBB participants were available, including a total of 3,724 cases and 285,622 healthy controls.
      • Anstee Q.M.
      • Darlay R.
      • Cockell S.
      • Meroni M.
      • Govaere O.
      • Tiniakos D.
      • et al.
      Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort.
      ,
      • Namjou B.
      • Lingren T.
      • Huang Y.
      • Parameswaran S.
      • Cobb B.L.
      • Stanaway I.B.
      • et al.
      GWAS and enrichment analyses of non-alcoholic fatty liver disease identify new trait-associated genes and pathways across eMERGE Network.
      We estimated the causal effect on NAFLD in each NAFLD GWAS and combined the MR estimates using meta-analysis. A bi-directional 2-sample MR framework was developed and the multiplicative random-effects model was adopted to evaluate the causal effects. Besides, weighted median, MR-Egger and MR-PRESSO methods were adopted as sensitivity analyses.
      • Verbanck M.
      • Chen C.Y.
      • Neale B.
      • Do R.
      Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases.
      Explicitly, genetically elevated ALM and grip strength levels could decrease the risk of NAFLD in the FinnGen NAFLD GWAS, however, such causal associations were not significant in the other 2 NAFLD GWASs (Fig. 1). The meta-analysis of these MR estimates indicated that none of the genetically elevated sarcopenia-associated traits was causally associated with the risk of NAFLD (Fig. 1). It should be noted that genetically elevated ALM could marginally reduce the risk of NAFLD in the meta-analysis (odds ratio 0.961; 95% CI 0.921–1.002). The reverse MR analysis suggested the genetic predisposition to NAFLD could not affect the levels of grip strength and ALM. The weighted median and MR-Egger analyses also suggested the null associations between genetically predicted sarcopenia-associated traits and NAFLD. The MR-PRESSO methods detected outliers of ALM while the results were not significant after removal of them. There was neither heterogeneity nor horizontal pleiotropy in MR estimates (Cochranes’s Q p value >0.05 and MR-Egger intercept p value >0.05). After adjusting for body mass index, type 2 diabetes, total cholesterol and blood pressure, the MR results remained insignificant. The current evidence from MR analyses seemed not to support the causal association of ALM and grip strength with NAFLD except in the FinnGen cohort.
      Figure thumbnail gr1
      Fig. 1The forest plot of forward and reverse MR estimates.
      (A) The outcome was NAFLD, and META represents the meta-analysis of MR estimates. (B) The effect size was beta value. NAFLD, non-alcoholic fatty liver disease; MR, Mendelian randomization.
      Generally, our MR analyses indicated null causal associations between ALM, grip strength and NAFLD. This conclusion contradicts that derived by Petermann-Rocha et al. There are a few explanations for this: (1) such causal associations could vary between different populations since we observed them in the UKBB and FinnGen while not in the meta-analysis; (2) Petermann-Rocha et al. were mainly focused on severe NAFLD while a broader definition of NAFLD was used in our study; (3) Petermann-Rocha et al. reported a non-linear association of muscle mass and grip strength with severe NAFLD; however, we could not directly estimate the non-linear causal effect in the MR setting since it would require individual-level data which were unavailable in our study.
      • Sun Y.Q.
      • Burgess S.
      • Staley J.R.
      • Wood A.M.
      • Bell S.
      • Kaptoge S.K.
      • et al.
      Body mass index and all cause mortality in HUNT and UK Biobank studies: linear and non-linear mendelian randomisation analyses.
      Besides, it should be noted that observational studies might be biased by unmeasured confounders and its associations were not casual. Although MR design can reduce the bias caused by such unmeasured confounders and give causal estimates, the magnitude of exposure was determined genetically and was not equal to the exposure in traditional observational studies, which usually lead to a null association in MR analysis. Further investigations within a causal framework should be encouraged with larger sample sizes that can give robust casual estimates.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      L.C acquired the data and performed the main MR analyses. Z.F drafted the mansucript and cheked the intergrity of data analysis. G.L propsoed the idea, revised the manuscript and was responsible for the integrity of data acquisition and statistical analyses.

      Data availability statement

      All GWAS summary statistics can be downloaded from open GWAS for expsoures (https://gwas.mrcieu.ac.uk/) and GWAS catalog (https://www.ebi.ac.uk/gwas/). These data can be used without restriction except for identifying individual-level information.

      Conflict of interest

      All authors declared that no potential conflicts of interest should be disclosed in this study.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Acknowledgements

      We want to acknowledge the participants and investigators of the FinnGen study. We want to thank MRC-IEU for making UK Biobank GWAS summary statistics openly available. Besides, we would like to thank all the other investigators for making summary statistics openly available.

      Supplementary data

      The following are the supplementary data to this article:

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        Associations of muscle mass and grip strength with severe NAFLD: a prospective study of 333,295 UK Biobank participants.
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