A novel framework to build saliva-based DNA methylation biomarkers: quantifying systemic chronic inflammation as a case study

• Published in: bioRxiv
• Main Authors: Schmunk, Lisa J, Call, Toby P, Mccartney, Daniel L, Hira Javaid, Hastings, Waylon J, Jovicevic, Vanja, Drago Kojadinovic, Tomkinson, Natacha, Zlamalova, Eliska, Mcgee, Kirsty C, Sullivan, Jack, Campbell, Archie, Mcintosh, Andrew M, Óvári, Veronika, Wishart, Karl, Behrens, Christian E, Stone, Emma, Gavrilov, Miloš, Thompson, Rob, Hurdle Bio-Infrastructure Team, Jackson, Thomas, Lord, Janet M, Stubbs, Thomas M, Marioni, Riccardo E, Martin-Herranz, Daniel E
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 23.12.2023; Cold Spring Harbor Laboratory
• Edition: 1.1
• Subjects: Bioinformatics; Biomarkers; Blood; C-reactive protein; DNA methylation; Electronic medical records; Employees; Epigenetics; Health care; Immunosenescence; Inflammation; Molecular modelling; Saliva; Systemic chronic inflammation (SCI); Biomarker; Ageing; Machine learning; DNA methylation; Inflammageing; Epigenetic Clock
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2023.12.21.572866

Accessible and non-invasive biomarkers that measure human ageing processes and the risk of developing age-related disease are paramount in preventative healthcare. In this study, we describe a novel framework to train saliva-based DNA methylation (DNAm) biomarkers that are reproducible and biologically interpretable. By leveraging a reliability dataset with replicates across tissues, we demonstrate that it is possible to transfer knowledge from blood DNAm data to saliva DNAm data using DNAm proxies of blood proteins (EpiScores). We then apply these methods to create a new saliva-based epigenetic clock (InflammAge) that quantifies systemic chronic inflammation (SCI) in humans. Using a large blood DNAm human cohort with linked electronic health records and over 18,000 individuals (Generation Scotland), we demonstrate that InflammAge significantly associates with all-cause mortality, disease outcomes, lifestyle factors and immunosenescence; in many cases outperforming the widely used SCI biomarker C-reactive protein (CRP). We propose that our biomarker discovery framework and InflammAge will be useful to improve our understanding of the molecular mechanisms underpinning human ageing and to assess the impact of gero-protective interventions.Competing Interest StatementLJS, HJ, VJ, DK, NT, EZ, ES, MG and the Hurdle bio-infrastructure team are employees and TPC, RT, TMS and DEMH are co-founders and shareholders at Chronomics Ltd., a company focused on multi-omics and epigenetic biomarker development and diagnostic infrastructure. VO and KW are employees at Bayer Consumer Care AG. CEB is an employee at Bayer HealthCare LLC. JML and WJH declare their roles as consultants for Bayer Consumer Care AG. Both report receiving consultancy fees from Bayer Consumer Care AG during the preparation of the study. Bayer Consumer Care AG financially supported this work. REM acts as a scientific consultant for Optima Partners and is an advisor to the Epigenetic Clock Development Foundation. All other authors declare no competing interests.