1. Epidemiology and Global Health
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Association of lipid-lowering drugs with COVID-19 outcomes from a Mendelian randomization study

  1. Wuqing Huang
  2. Jun Xiao
  3. Jianguang Ji  Is a corresponding author
  4. Liangwan Chen  Is a corresponding author
  1. Fujian Medical University, China
  2. Fujian Medical University Union Hospital, China
  3. Lund University, Sweden
Research Article
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Cite this article as: eLife 2021;10:e73873 doi: 10.7554/eLife.73873

Abstract

Background: Lipid metabolism plays an important role in viral infections. We aimed to assess the causal effect of lipid-lowering drugs (HMGCR inhibitiors, PCSK9 inhibitiors and NPC1L1 inhibitior) on COVID-19 outcomes using 2-sample Mendelian Randomization (MR) study.

Methods: We used two kinds of genetic instruments to proxy the exposure of lipid-lowering drugs, including eQTLs of drugs target genes, and genetic variants within or nearby drugs target genes associated with LDL cholesterol from GWAS. Summary-data-based MR (SMR) and inverse-variance weighted MR (IVW-MR) were used to calculate the effect estimates.

Results: SMR analysis found that a higher expression of HMGCR was associated with a higher risk of COVID-19 hospitalization (OR=1.38, 95%CI=1.06-1.81). Similarly, IVW-MR analysis observed a positive association between HMGCR-mediated LDL cholesterol and COVID-19 hospitalization (OR=1.32, 95%CI=1.00-1.74). No consistent evidence from both analyses was found for other associations.

Conclusions: This 2-sample MR study suggested a potential causal relationship between HMGCR inhibition and the reduced risk of COVID-19 hospitalization.

Funding: Fujian Province Major Science and Technology Program.

Data availability

Individual-level data cannot be provided but the raw data of the eQTLGen Consortium, GTEx and COVID-19 Host Genetics Initiative can be acessed at https://www.eqtlgen.org/, https://gtexportal.org/, and https://www.covid19hg.org/ , respectively. Summary-level GWAS or eQTL data and code used to produce main results have been uploaded to GitHub(https://github.com/WH57/lipid_covid19.git). All MR results and GWAS or eQTL associations of selected SNPs were provided in theSupplementary File 1 - Tables 2 to 4.

The following previously published data sets were used

Article and author information

Author details

  1. Wuqing Huang

    Department of Epidemiology and Health Statistics, Fujian Medical University, Fuzhou, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7616-8622
  2. Jun Xiao

    Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5046-5493
  3. Jianguang Ji

    Center for Primary Health Care Research, Department of Clinical Sciences, Lund University, Malmö, Sweden
    For correspondence
    jianguang.ji@med.lu.se
    Competing interests
    The authors declare that no competing interests exist.
  4. Liangwan Chen

    Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, China
    For correspondence
    chenliangwan@fjmu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4211-3842

Funding

Fujian Province Major Science and Technology Program (2018YZ001-1)

  • Liangwan Chen

The funder had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: This 2-sample MR study is based on publicly available summary-level data from genome-wide association studies (GWASs) and expression quantitative trait loci (eQTLs) studies. All these studies had been approved by the relevant institutional review boards and participants had provided informed consents.

Reviewing Editor

  1. Edward D Janus, University of Melbourne, Australia

Publication history

  1. Preprint posted: July 24, 2021 (view preprint)
  2. Received: September 14, 2021
  3. Accepted: November 22, 2021
  4. Accepted Manuscript published: December 6, 2021 (version 1)
  5. Version of Record published: December 24, 2021 (version 2)

Copyright

© 2021, Huang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Further reading

Further reading

    1. Epidemiology and Global Health
    Ceereena Ubaida-Mohien et al.
    Research Article Updated

    Background:

    Master athletes (MAs) prove that preserving a high level of physical function up to very late in life is possible, but the mechanisms responsible for their high function remain unclear.

    Methods:

    We performed muscle biopsies in 15 octogenarian world-class track and field MAs and 14 non-athlete age/sex-matched controls (NA) to provide insights into mechanisms for preserving function in advanced age. Muscle samples were assessed for respiratory compromised fibers, mitochondrial DNA (mtDNA) copy number, and proteomics by liquid-chromatography mass spectrometry.

    Results:

    MA exhibited markedly better performance on clinical function tests and greater cross-sectional area of the vastus lateralis muscle. Proteomics analysis revealed marked differences, where most of the ~800 differentially represented proteins in MA versus NA pertained to mitochondria structure/function such as electron transport capacity (ETC), cristae formation, mitochondrial biogenesis, and mtDNA-encoded proteins. In contrast, proteins from the spliceosome complex and nuclear pore were downregulated in MA. Consistent with proteomics data, MA had fewer respiratory compromised fibers, higher mtDNA copy number, and an increased protein ratio of the cristae-bound ETC subunits relative to the outer mitochondrial membrane protein voltage-dependent anion channel. There was a substantial overlap of proteins overrepresented in MA versus NA with proteins that decline with aging and that are higher in physically active than sedentary individuals. However, we also found 176 proteins related to mitochondria that are uniquely differentially expressed in MA.

    Conclusions:

    We conclude that high function in advanced age is associated with preserving mitochondrial structure/function proteins, with underrepresentation of proteins involved in the spliceosome and nuclear pore complex. Whereas many of these differences in MA appear related to their physical activity habits, others may reflect unique biological (e.g., gene, environment) mechanisms that preserve muscle integrity and function with aging.

    Funding:

    Funding for this study was provided by operating grants from the Canadian Institutes of Health Research (MOP 84408 to TT and MOP 125986 to RTH). This work was supported in part by the Intramural Research Program of the National Institute on Aging, NIH, Baltimore, MD, USA.

    1. Epidemiology and Global Health
    Toby Mansell et al.
    Research Article

    Background:

    The risk of adult onset cardiovascular and metabolic (cardiometabolic) disease accrues from early life. Infection is ubiquitous in infancy and induces inflammation, a key cardiometabolic risk factor, but the relationship between infection, inflammation, and metabolic profiles in early childhood remains unexplored. We investigated relationships between infection and plasma metabolomic and lipidomic profiles at age 6 and 12 months, and mediation of these associations by inflammation.

    Methods:

    Matched infection, metabolomics, and lipidomics data were generated from 555 infants in a pre-birth longitudinal cohort. Infection data from birth to 12 months were parent-reported (total infections at age 1, 3, 6, 9, and 12 months), inflammation markers (high-sensitivity C-reactive protein [hsCRP]; glycoprotein acetyls [GlycA]) were quantified at 12 months. Metabolic profiles were 12-month plasma nuclear magnetic resonance metabolomics (228 metabolites) and liquid chromatography/mass spectrometry lipidomics (776 lipids). Associations were evaluated with multivariable linear regression models. In secondary analyses, corresponding inflammation and metabolic data from birth (serum) and 6-month (plasma) time points were used.

    Results:

    At 12 months, more frequent infant infections were associated with adverse metabolomic (elevated inflammation markers, triglycerides and phenylalanine, and lower high-density lipoprotein [HDL] cholesterol and apolipoprotein A1) and lipidomic profiles (elevated phosphatidylethanolamines and lower trihexosylceramides, dehydrocholesteryl esters, and plasmalogens). Similar, more marked, profiles were observed with higher GlycA, but not hsCRP. GlycA mediated a substantial proportion of the relationship between infection and metabolome/lipidome, with hsCRP generally mediating a lower proportion. Analogous relationships were observed between infection and 6-month inflammation, HDL cholesterol, and apolipoprotein A1.

    Conclusions:

    Infants with a greater infection burden in the first year of life had proinflammatory and proatherogenic plasma metabolomic/lipidomic profiles at 12 months of age that in adults are indicative of heightened risk of cardiovascular disease, obesity, and type 2 diabetes. These findings suggest potentially modifiable pathways linking early life infection and inflammation with subsequent cardiometabolic risk.

    Funding:

    The establishment work and infrastructure for the BIS was provided by the Murdoch Children’s Research Institute (MCRI), Deakin University, and Barwon Health. Subsequent funding was secured from National Health and Medical Research Council of Australia (NHMRC), The Shepherd Foundation, The Jack Brockhoff Foundation, the Scobie & Claire McKinnon Trust, the Shane O’Brien Memorial Asthma Foundation, the Our Women’s Our Children’s Fund Raising Committee Barwon Health, the Rotary Club of Geelong, the Minderoo Foundation, the Ilhan Food Allergy Foundation, GMHBA, Vanguard Investments Australia Ltd, and the Percy Baxter Charitable Trust, Perpetual Trustees. In-kind support was provided by the Cotton On Foundation and CreativeForce. The study sponsors were not involved in the collection, analysis, and interpretation of data; writing of the report; or the decision to submit the report for publication. Research at MCRI is supported by the Victorian Government’s Operational Infrastructure Support Program. This work was also supported by NHMRC Senior Research Fellowships to ALP (1008396); DB (1064629); and RS (1045161) , NHMRC Investigator Grants to ALP (1110200) and DB (1175744), NHMRC-A*STAR project grant (1149047). TM is supported by an MCRI ECR Fellowship. SB is supported by the Dutch Research Council (452173113).