Integrated analyses of growth differentiation Factor-15 concentration and cardiometabolic diseases in humans
Abstract
Growth differentiation factor 15 (GDF15) is a stress response cytokine that is elevated in several cardiometabolic diseases and has attracted interest as a potential therapeutic target. To further explore the association of GDF15 with human disease, we conducted a broad study into the phenotypic and genetic correlates of GDF15 concentration in up to 14,099 individuals. Assessment of 772 traits across 6,610 participants in FINRISK identified associations of GDF15 concentration with a range of phenotypes including all-cause mortality, cardiometabolic disease, respiratory diseases and psychiatric disorders as well as inflammatory markers. A meta-analysis of genome-wide association studies (GWAS) of GDF15 concentration across 3 different assay platforms (n=14,099) confirmed significant heterogeneity due to a common missense variant rs1058587 in GDF15, potentially due to epitope-binding artefacts. After conditioning on rs1058587, statistical fine-mapping identified 4 independent putative causal signals at the locus. Mendelian randomisation (MR) analysis found evidence of a causal relationship between GDF15 concentration and high-density lipoprotein (HDL) but not body mass index (BMI). Using reverse MR, we identified a potential causal association of BMI on GDF15 (IVW pFDR=0.0040). Taken together, our data do not support a role for elevated GDF15 concentrations as a causal factor in human cardiometabolic disease but support its role as a biomarker of metabolic stress.
Data availability
Participant-level genotype and phenotype data from UK Biobank are available by application: https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access.Participant-level genotype and phenotype data (as part of the FinnGen consortium) are available by application: https://www.finngen.fi/en/access_results.INTERVAL-SomaScan participant-level genotype and protein data, and full summary association results from the genetic analysis are available through the European Genotype Archive (accession number EGA00001002555). Summary association results are also publically available at http://www.phpc.cam.ac.uk/ceu/proteins/, through PhenoScanner (http://www.phenoscanner.medschl.cam.ac.uk) and from the NHGRI-EBI GWAS Catalog (https://www.ebi.ac.uk/gwas/downloads/summary-statistics).INTERVAL-Olink summary association results are publically available at http://www.phpc.cam.ac.uk/ceu/proteins/.
Article and author information
Author details
Funding
NIHR Cambridge Biomedical Research Centre (BRC-1215-20014)
- Rachel MY Ong
Sydäntutkimussäätiö
- Veikko Salomaa
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Edward D Janus, University of Melbourne, Australia
Ethics
Human subjects: FINRISK study was approved by the Ethics Committee of Helsinki and Uusimaa Hospital District.Informed consent was obtained from all participants and the INTERVAL study was approved by the National Research Ethics Service (11/EE/0538).All study participants provided informed consent and the UK Biobank has approval from the North-West Multi-centre Research Ethics Committee (MREC; 11/NW/0382).
Version history
- Received: December 10, 2021
- Preprint posted: December 16, 2021 (view preprint)
- Accepted: August 1, 2022
- Accepted Manuscript published: August 2, 2022 (version 1)
- Version of Record published: August 19, 2022 (version 2)
Copyright
© 2022, Lemmelä 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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Further reading
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- Epidemiology and Global Health
Background:
The aim of our study was to test the hypothesis that the community contact tracing strategy of testing contacts in households immediately instead of at the end of quarantine had an impact on the transmission of SARS-CoV-2 in schools in Reggio Emilia Province.
Methods:
We analysed surveillance data on notification of COVID-19 cases in schools between 1 September 2020 and 4 April 2021. We have applied a mediation analysis that allows for interaction between the intervention (before/after period) and the mediator.
Results:
Median tracing delay decreased from 7 to 3.1 days and the percentage of the known infection source increased from 34–54.8% (incident rate ratio-IRR 1.61 1.40–1.86). Implementation of prompt contact tracing was associated with a 10% decrease in the number of secondary cases (excess relative risk –0.1 95% CI –0.35–0.15). Knowing the source of infection of the index case led to a decrease in secondary transmission (IRR 0.75 95% CI 0.63–0.91) while the decrease in tracing delay was associated with decreased risk of secondary cases (1/IRR 0.97 95% CI 0.94–1.01 per one day of delay). The direct effect of the intervention accounted for the 29% decrease in the number of secondary cases (excess relative risk –0.29 95%–0.61 to 0.03).
Conclusions:
Prompt contact testing in the community reduces the time of contact tracing and increases the ability to identify the source of infection in school outbreaks. Although there are strong reasons for thinking it is a causal link, observed differences can be also due to differences in the force of infection and to other control measures put in place.
Funding:
This project was carried out with the technical and financial support of the Italian Ministry of Health – CCM 2020 and Ricerca Corrente Annual Program 2023.
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