Cross-Sectional Blood Metabolite Markers of Hypertension: A Multicohort Analysis of 44,306 Individuals from the COnsortium of METabolomics Studies
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Hypertension is the main modifiable risk factor for cardiovascular morbidity and mortality but discovering molecular mechanisms for targeted treatment has been challenging. Here we investigate associations of blood metabolite markers with hypertension by integrating data from nine intercontinental cohorts from the COnsortium of METabolomics Studies. We included 44,306 individuals with circulating metabolites (up to 813). Metabolites were aligned and inverse normalised to allow intra-platform comparison. Logistic models adjusting for covariates were performed in each cohort and results were combined using random-effect inverse-variance meta-analyses adjusting for multiple testing. We further conducted canonical pathway analysis to investigate the pathways underlying the hypertension-associated metabolites. In 12,479 hypertensive cases and 31,827 controls without renal impairment, we identified 38 metabolites, associated with hypertension after adjusting for age, sex, body mass index, ethnicity, and multiple testing. Of these, 32 metabolite associations, predominantly lipid (steroids and fatty acyls) and organic acids (amino-, hydroxy-, and keto-acids) remained after further adjusting for comorbidities and dietary intake. Among the identified metabolites, 5 were novel, including 2 bile acids, 2 glycerophospholipids, and ketoleucine. Pathway analysis further implicates the role of the amino-acids, serine/glycine, and bile acids in hypertension regulation. In the largest cross-sectional hypertension-metabolomics study to date, we identify 32 circulating metabolites (of which 5 novel and 27 confirmed) that are potentially actionable targets for intervention. Further in-vivo studies are needed to identify their specific role in the aetiology or progression of hypertension.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 601 |
| Tidsskrift | Metabolites |
| Vol/bind | 12 |
| Udgave nummer | 7 |
| Antal sider | 14 |
| ISSN | 2218-1989 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
This work was funded by the Chronic Disease Research Foundation (CDRF) and the MRC AIM-HY project grant TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Global Ltd. and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London). The Health Aging and Body Composition Study was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (NIA) and National Cancer Institute; the NIA Contracts N01-AG-6–2101, N01-AG-6–2103, and N01-AG-6–2106; NIA Grant R01-AG028050, National Institute of Nursing Research Grant R01-NR-012459, the Wake Forest University Claude D. Pepper Older Americans for Independence Center (1P30AG21332); and the Pittsburgh Claude D. Pepper Center (P30 AG024827). Qatar Biobank is supported by the Qatar Foundation. The Whitehall II study is supported by the Wellcome Trust (221854/Z/20/Z), the UK Medical Research Council (MR/S011676/1), and the National Institute on Aging (NIH), US (R01AG056477). The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, 75N92022D00005). The Caerphlliy Propsective Study (CaPS) was undertaken by the former MRC Epidemiology Unit (South Wales) and was funded by the Medical Research Council of the United Kingdom. The University of Bristol Medical School act as the data custodians (https://www.bristol.ac.uk/population-health-sciences/projects/caerphilly/, accessed on 8 June 2022) The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. Deborah Lawlor, and Neil Goulding contributed to this work and will serve as guarantors for the ALSPAC contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf, accessed on 8 June 2022). Work from ALSPAC authors was specifically funded by the British Heart Foundation (Grant ref: SP/07/008/24066 and CS/15/6/31468), Wellcome Trust (Grant ref: WT092830/Z/10/Z), Wellcome Trust and MRC (Grant ref: 092731) and NIHR (Grant ref: NF-SI-0611–10196). C.M. is funded by the Chronic Disease Research Foundation and by the MRC AIM-HY project grant. P.L. is funded by the Chronic Disease Research Foundation (CDRF–15/2018). A.N is funded by the Chronic Disease Research Foundation. M.M. is funded by the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. R.A.M is funded by the Michael Smith Foundation for Health Research (grant 17644). NG and DAL work in a Unit that receives support from the University of Bristol and the MRC (MC_UU_00011/6). K.S. is supported by the Biomedical Research Program at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation, and by Qatar National Research Fund (QNRF) grant NPRP11C-0115–180010. The statements made herein are solely the responsibility of the authors. Bo Chawes has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 946228). M.K. is supported by the Wellcome Trust (221854/Z/20/Z), the UK Medical Research Council (MR/S011676/1), Academy of Finland (350426), and the National Institute on Aging (NIH), US (R01AG056477). JVL was supported by Academy of Finland (339568).
Funding Information:
Funding: This work was funded by the Chronic Disease Research Foundation (CDRF) and the MRC AIM-HY project grant TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Global Ltd. and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London). The Health Aging and Body Composition Study was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (NIA) and National Cancer Institute; the NIA Contracts N01-AG-6–2101, N01-AG-6–2103, and N01-AG-6– 2106; NIA Grant R01-AG028050, National Institute of Nursing Research Grant R01-NR-012459, the Wake Forest University Claude D. Pepper Older Americans for Independence Center (1P30AG21332); and the Pittsburgh Claude D. Pepper Center (P30 AG024827). Qatar Biobank is supported by the Qatar Foundation. The Whitehall II study is supported by the Wellcome Trust (221854/Z/20/Z), the UK Medical Research Council (MR/S011676/1), and the National Institute on Aging (NIH), US (R01AG056477). The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, 75N92022D00005). The Caerphlliy Propsective Study (CaPS) was undertaken by the former MRC Epidemiology Unit (South Wales) and was funded by the Medical Research Council of the United Kingdom. The University of Bristol Medical School act as the data custodians (https://www.bristol.ac.uk/population-health-sciences/projects/ caerphilly/, accessed on 8 June 2022) The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. Deborah Lawlor, and Neil Goulding contributed to this work and will serve as guarantors for the ALSPAC contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf, accessed on 8 June 2022). Work from ALSPAC authors was specifically funded by the British Heart Foundation (Grant ref: SP/07/008/24066 and CS/15/6/31468), Wellcome Trust (Grant ref: WT092830/Z/10/ Z), Wellcome Trust and MRC (Grant ref: 092731) and NIHR (Grant ref: NF-SI-0611-10196). C.M. is funded by the Chronic Disease Research Foundation and by the MRC AIM-HY project grant. P.L. is funded by the Chronic Disease Research Foundation (CDRF–15/2018). A.N is funded by the Chronic Disease Research Foundation. M.M. is funded by the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. R.A.M is funded by the Michael Smith Foundation for Health Research (grant 17644). NG and DAL work in a Unit that receives support from the University of Bristol and the MRC (MC_UU_00011/6). K.S. is supported by the Biomedical Research Program at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation, and by Qatar National Research Fund (QNRF) grant NPRP11C-0115-180010. The statements made herein are solely the responsibility of the authors. Bo Chawes has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 946228). M.K. is supported by the Wellcome Trust (221854/Z/20/Z), the UK Medical Research Council (MR/S011676/1), Academy of Finland (350426), and the National Institute on Aging (NIH), US (R01AG056477). JVL was supported by Academy of Finland (339568).
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© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
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