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Ritchie SC, Kettunen J, Brozynska M, Nath AP, Havulinna AS, Männistö S, et al. (2019) Elevated serum alpha-1 antitrypsin is a major component of GlycA-associated risk for future morbidity and mortality. PLoS ONE 14(10): e0223692. https://doi.org/10.1371/journal.pone.0223692

Elevated serum alpha-1 antitrypsin is a major component of GlycA-associated risk for future morbidity and mortality

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Author: Ritchie, Scott C.1,2,3; Kettunen, Johannes4,5,6; Brozynska, Marta1,2;
Organizations: 1Cambridge Baker Systems Genomics Initiative, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
2Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
3Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia
4Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland
5National Institute for Health and Welfare, Helsinki, Finland
6NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
7Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
8Population Health Science, Bristol Medical School, University of Bristol, Bristol, United Kingdom
9Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
10Systems Epidemiology Lab, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
11Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, The Alfred Hospital, Monash University, Melbourne, Victoria, Australia
12Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia, School of BioSciences, The University of Melbourne, Parkville, Victoria, Australia
13Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
14Nightingale Health Ltd, Helsinki, Finland
15School of BioSciences, The University of Melbourne, Parkville, Victoria, Australia
16The Alan Turing Institute, London, United Kingdom
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.9 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe202003279537
Language: English
Published: Public Library of Science, 2019
Publish Date: 2020-03-27
Description:

Abstract

Background: GlycA is a nuclear magnetic resonance (NMR) spectroscopy biomarker that predicts risk of disease from myriad causes. It is heterogeneous; arising from five circulating glycoproteins with dynamic concentrations: alpha-1 antitrypsin (AAT), alpha-1-acid glycoprotein (AGP), haptoglobin (HP), transferrin (TF), and alpha-1-antichymotrypsin (AACT). The contributions of each glycoprotein to the disease and mortality risks predicted by GlycA remain unknown.

Methods: We trained imputation models for AAT, AGP, HP, and TF from NMR metabolite measurements in 626 adults from a population cohort with matched NMR and immunoassay data. Levels of AAT, AGP, and HP were estimated in 11,861 adults from two population cohorts with eight years of follow-up, then each biomarker was tested for association with all common endpoints. Whole blood gene expression data was used to identify cellular processes associated with elevated AAT.

Results: Accurate imputation models were obtained for AAT, AGP, and HP but not for TF. While AGP had the strongest correlation with GlycA, our analysis revealed variation in imputed AAT levels was the most predictive of morbidity and mortality for the widest range of diseases over the eight year follow-up period, including heart failure (meta-analysis hazard ratio = 1.60 per standard deviation increase of AAT, P-value = 1×10−10), influenza and pneumonia (HR = 1.37, P = 6×10−10), and liver diseases (HR = 1.81, P = 1×10−6). Transcriptional analyses revealed association of elevated AAT with diverse inflammatory immune pathways.

Conclusions: This study clarifies the molecular underpinnings of the GlycA biomarker’s associated disease risk, and indicates a previously unrecognised association between elevated AAT and severe disease onset and mortality.

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Series: PLoS one
ISSN: 1932-6203
ISSN-E: 1932-6203
ISSN-L: 1932-6203
Volume: 14
Issue: 10
Article number: e0223692
DOI: 10.1371/journal.pone.0223692
OADOI: https://oadoi.org/10.1371/journal.pone.0223692
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
317 Pharmacy
Subjects:
Article
Funding: This study was supported by funding from National Health and Medical Research Council (NHMRC) grant APP1062227 and by the Victorian Government’s Operational Infrastructure Support (OIS) program, as well as core funding from the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG/13/13/30194; RG/18/13/33946) and the National Institute for Health Research [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust] [*]. M.I. and S.C.R. were funded by the National Institute for Health Research [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust] [*]. M.I. was supported by an NHMRC and Australian Heart Foundation Career Development Fellowship (no. 1061435). S.C.R. was supported by an Australian Postgraduate Award. G.A. was supported by an NHMRC Early Career Fellowship (no. 1090462). J.K. and P.W. were funded by Academy of Finland (grant numbers 297338 and 307247, 312476, and 312477) and Novo Nordisk Foundation (NNF17OC0026062 and 15998). V.S. was supported by the Finnish Foundation for Cardiovascular Research. M.A.K. was supported by the Sigrid Juselius Foundation, Finland. M.A.K. works in a Unit that is supported by the University of Bristol and UK Medical Research Council (MC_UU_12013/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. *The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.
Academy of Finland Grant Number: 297338
307247
Detailed Information: 297338 (Academy of Finland Funding decision)
307247 (Academy of Finland Funding decision)
Copyright information: © 2019 Ritchie et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
  https://creativecommons.org/licenses/by/4.0/