A novel DNA methylation-based surrogate biomarker for chronic systemic inflammation (InfLaMeS): results from the Health and Retirement Study

ABSTRACT Chronic low-grade systemic inflammation is a risk factor for chronic diseases and mortality and is an important biomarker in health research. DNA methylation (DNAm) surrogate biomarkers are valuable exposure, risk factor and health outcome predictors in studies where the measures cannot be measured directly and often perform as well or better than direct measure. We generated a DNAm surrogate biomarker for chronic, systemic inflammation from a systemic inflammation latent variable of seven inflammatory markers and evaluated its performance relative to measured inflammatory biomarkers in predicting several age-associated outcomes of interest, including mortality, activities of daily living and multimorbidity in the Health and Retirement Study (HRS). The DNAm surrogate, Inflammation Latent Variable Methylation Surrogate (InfLaMeS), correlated with seven individual inflammation markers (r= −0.2-0.6) and performed as well or better to the systemic inflammation latent variable measure when predicting multimorbidity, disability, and 4-year mortality in HRS. Findings were validated in an external cohort, The Irish Longitudinal Study of Ageing. These results suggest that InfLaMeS provides a robust alternative to measured blood-chemistry measures of inflammation with broad applicability in instances where values of inflammatory markers are not measured but DNAm data is available. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by U01AG073289, R01AG068937, R01AG060110, and R01AG071071. The Health and Retirement Study is sponsored by the National Institute on Aging (U01AG009740) and conducted by the University of Michigan. SFI US-Ireland Research and Development Partnership (Grant Number 19/US/3615) (BH, CMcC, RAK). TILDA is supported by the Irish Government, the Atlantic Philanthropies, and the Health Research Board. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: HRS data are available on the HRS website [https://hrs.isr.umich.edu/] and in the HRS NIAGADS repository [https://dss.niagads.org/datasets/ng00153/]. TILDA data are available from TILDA [https://tilda.tcd.ie/data/accessing-data/]. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability HRS data are available on the HRS website [https://hrs.isr.umich.edu/] and in the HRS NIAGADS repository [https://dss.niagads.org/datasets/ng00153/]. TILDA data are available from TILDA [https://tilda.tcd.ie/data/accessing-data/]. https://tilda.tcd.ie/data/accessing-data/