DNAm scores for serum GDF15 and NT-proBNP levels associate with a range of traits affecting the body and brain

Abstract

Background: Plasma growth differentiation factor 15 (GDF15) and Nterminal proBtype natriuretic peptide (NTproBNP) are cardiovascular biomarkers that associate with a range of diseases. Epigenetic scores (EpiScores) for GDF15 and NTproBNP may provide new routes for risk stratification. Results: In the Generation Scotland cohort (N ≥ 16,963), GDF15 levels were associated with incident dementia, ischaemic stroke and type 2 diabetes, whereas NTproBNP levels were associated with incident ischaemic heart disease, ischaemic stroke and type 2 diabetes (all PFDR < 0.05). Bayesian Epigenome wide association studies (EWAS) identified 12 and 4 DNA methylation (DNAm) CpG sites associated (Posterior Inclusion Probability [PIP] > 95%) with levels of GDF15 and NTproBNP, respectively. EpiScores for GDF15 and NTproBNP that were trained in a subset of the population. The GDF15 EpiScore replicated protein associations with incident dementia, type 2 diabetes and ischaemic stroke in the Generation Scotland test set (Hazard Ratios (HR) range 1.36 to 1.41, PFDR <0.03). The EpiScore for NTproBNP replicated the protein association with type 2 diabetes, but failed to replicate an association with ischaemic stroke. EpiScores explained comparable variance in protein levels across both the Generation Scotland test set and the external LBC1936 test cohort (R2 range of 5.7-12.2%). In LBC1936, both EpiScores were associated with indicators of poorer brain health. Neither EpiScore was associated with incident dementia in the LBC1936 population. Conclusions: EpiScores for serum levels of GDF15 and NtproBNP associate with body and brain health traits. These EpiScores are provided as potential tools for disease risk stratification.

Epigenetic scores indicate differences in the proteome of preterm infants

“…The study has some limitations. The EpiScores used were developed in adult cohorts [26–28,37] and have not been validated in neonatal populations with neonatal protein levels, although we have previously established that neonatal DNAmCRP scores correlate with cumulative inflammatory exposures [32]. Further studies that evaluate serial blood protein levels with EpiScores could be informative but would need to rely on small volume samples taken during time of venepuncture for clinical reasons, given the practical and ethical challenges of serial venepuncture for research purposes in neonates.…”

“…Further studies that evaluate serial blood protein levels with EpiScores could be informative but would need to rely on small volume samples taken during time of venepuncture for clinical reasons, given the practical and ethical challenges of serial venepuncture for research purposes in neonates. The EpiScores were also trained using blood samples [26–28,37], whereas we have projected these scores into saliva samples. However, previous studies have successfully used similar cross-tissue techniques [32,107,108], and in neonates saliva provides a non-invasive and accessible sample method.…”

“…For duplicate proteins, those developed using Olink platform-identified proteins (antibody-based assays) were prioritised over those from SOMAscan platforms (aptamer-based assays), due to specificity and reproducibility, and the variable correlation between the two methods [45–48] (for details see Supplementary eMethods, Additional File 1). In addition, we included EpiScores for growth and differentiation factor 15 (GDF15) and N-terminal-pro B-type natriuretic peptide (NTproBNP) [37], and CRP. The CRP EpiScore used was Barker et al ’s seven-CpG variation of Ligthart et al ’s CRP EpiScore [27,31], as this is known to correlate with birth GA, perinatal pro-inflammatory exposures, and neonatal brain development [32].…”

“…We investigated relationships between preterm birth, SES, and 104 EpiScores enriched for inflammation-related proteins [26–28,31,37]. We tested the following hypotheses: first, low GA is associated with differences in EpiScores; second, SES is correlated with EpiScores, and interacts with birth GA, but the relationship is attenuated by inflammatory disease burden in preterm infants.…”