Circulating causal protein networks linked to future risk of myocardial infarction

Abstract Variations in blood protein levels have been associated with a broad spectrum of complex diseases, including atherosclerotic cardiovascular disease (ACVD). These associations highlight the intricate interplay between local (e.g., cardiovascular) and systemic (non-cardiovascular) factors for the development of ACVD, emphasizing the need for a comprehensive, systems-level understanding of its etiology. To accomplish this, we developed a causal network inference framework by analyzing one of the largest serum proteomics studies to date, the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES), a prospective population-based study of 7,523 serum proteins measured in 5,376 older adults. To reconstruct a causal network of serum proteins, we used cis-acting protein quantitative trait loci (pQTLs) as instrumental variables to infer causal relationships between protein pairs, while accounting for potential unobserved confounding factors. We identified 185 causal protein subnetworks (FDR = 1%, n ≥ 10 members), which collectively interacted with 5,611 target proteins, offering valuable biological insights and an overview of systemic homeostasis. Several subnetworks, many of which interact to establish a hierarchy of directional relationships, were significantly associated with future myocardial infarction and/or its long-term complications like heart failure, as well as with key cardiometabolic traits that contribute to the onset of ACVD. Competing Interest Statement J.L., L.L.J., N.F. and A.P.O. are employees and stockholders of Novartis. All other authors have nothing to disclose. Funding Statement National Institute on Aging (NIA) contracts N01-AG-12100 and HHSN271201200022C for V. G. financed the study. V. G. received funding from the NIA (1R01AG065596-01A1), and IHA received a grant from the Icelandic Parliament. T.M. acknowledges support from the Research Council of Norway (project number 312045), the European Union Horizon Europe (European Innovation Council) (grant agreement number 101115381), and the L. Meltzers Hoyskolefond. 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: The AGES study was approved by the National Bioethics Committee in Iceland that acts as the institutional review board for the Icelandic Heart Association (approval number VSN-00-063, in accordance with the Helsinki Declaration) and by the US National Institutes of Health, National Institute on Aging Intramural Institutional Review Board. 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 Resource Availability Data from the AGES Reykjavik study are available through collaboration (AGES_data_request{at}hjarta.is) under a data usage agreement with the IHA. All access to data is controlled via the use of subject-signed informed consent authorization. The time it takes to respond to requests varies depending on their nature and circumstances of the request, but it will not exceed 14 working days. All data supporting the conclusions of the paper are presented in the main text and freely available through supplementary data to this manuscript. All code used in this study is accessible at the following repository: https://github.com/sbankier/AGES_causal_protein_networks.