Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities

Introduction Type 2 diabetes (T2D) is a heterogeneous disorder for which disease-causing pathways are incompletely understood. Here, we mapped genetic risk for T2D and its comorbidities to proteins, mechanistic pathways and clinical outcomes using proteogenomic data from a population-scale biobank and two randomized controlled trials. Methods We tested polygenic scores (PGS) for T2D and its cardiometabolic comorbidities, plus five partitioned T2D PGS (beta cell, lipodystrophy, liver lipid, obesity, and liver lipid), for association with 2,922 circulating proteins in 54,306 multi-ancestry participants (of which 42,452 were unrelated and without prevalent cardiometabolic disease) from the UK Biobank (UKB). Then, we tested the PGS-associated proteins for association with incident cardiometabolic complications in two cardiovascular outcome trials among T2D patients with proteogenomic data: EXSCEL (N=2,823) and DECLARE-TIMI 58 (N=915). We assessed causality using two-sample Mendelian randomization and mediation. Results We identified 839 unique proteins significantly associated with any T2D PGS and 1,005 proteins that were associated with at least one cardiometabolic PGS. Some PGS-associated proteins such as TFF3, EFEMP1, and MMP12 were in turn associated with renal and cardiovascular trial outcomes. PGS association patterns revealed shared pathways, e.g., complement cascade, cholesterol metabolism, IGF signaling. The proteins underlying these pathways, such as LPA, C1S, and IGFBP2, were consistently associated with clinical trial outcomes or identified via causal inference. Conclusions This proteogenomic study revealed proteins and mechanistic pathways underlying T2D and related comorbidities, advancing our understanding of T2D pathobiology and identifying putative biomarkers. All our results are available in an online data portal (). ### Competing Interest Statement D.P.L., M.G., D.M., D.V., X.J., I.A.G., S.P., J.O., A.N., and D.S.P. are employees of AstraZeneca and may hold AstraZeneca stock options. B.B.S. and H.R. are employees of Biogen and may hold stock options. C.D.W. is an employee of Janssen Pharmaceuticals, a Johnson & Johnson company, and may hold stock options. R.R.H. reports personal fees from Anji Pharmaceuticals, AstraZeneca and Novartis. R.J.M. received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Eli Lilly, Medtronic, Medable, Merck, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Relypsa, Respicardia, Roche, Rocket Pharmaceuticals, Sanofi, Verily, Vifor, Windtree Therapeutics, and Zoll. M.I. is a trustee of the Public Health Genomics (PHG) Foundation, a member of the Scientific Advisory Board of Open Targets and has research collaborations with Nightingale Health and Pfizer which are unrelated to this study. ### Funding Statement UK Biobank proteomics data was funded by a consortia of 13 participating pharmaceutical companies (Alnylam Pharmaceuticals, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Calico, Genentech, GlaxoSmithKline, The Janssen Pharmaceutical Companies of Johnson & Johnson, Novo Nordisk, Pfizer, Regeneron and Takeda). The DECLARE-TIMI 58 and EXSCEL clinical trial were funded by AstraZeneca. ### 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: Information on EXSCEL and DECLARE-TMI 58 trials can be found on [clinicaltrials.gov][1] ([NCT01144338][2] for EXSCEL and [NCT01144338][2] for DECLARE). The trial protocols were approved by institutional review board at each participating site. UK Biobank has approval from the North West Multi-centre Research Ethics Committee (MREC) as a Research Tissue Bank (RTB). 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][3]. 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 All data produced in the present study are available upon reasonable request to the authors. Polygenic scores will be uploaded to the PGS Catalog. [1]: http://clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01144338&atom=%2Fmedrxiv%2Fearly%2F2024%2F03%2F19%2F2024.03.15.24304200.atom [3]: http://ClinicalTrials.gov