@article{342fffea040e4bdb8d082a4ef370238a,
title = "Cystatin C is associated with adverse COVID-19 outcomes in diverse populations",
abstract = "COVID-19 has highly variable clinical courses. The search for prognostic host factors for COVID-19 outcome is a priority. We performed logistic regression for ICU admission against a polygenic score (PGS) for Cystatin C (CyC) production in patients with COVID-19. We analyzed the predictive value of longitudinal plasma CyC levels in an independent cohort of patients hospitalized with COVID-19. In four cohorts spanning European and African ancestry populations, we identified a significant association between CyC-production PGS and odds of critical illness (n cases=2,319), with the strongest association captured in the UKB cohort (OR 2.13, 95\% CI 1.58-2.87, p=7.12e-7). Plasma proteomics from an independent cohort of hospitalized COVID-19 patients (n cases = 131) demonstrated that CyC production was associated with COVID-specific mortality (p=0.0007). Our findings suggest that CyC may be useful for stratification of patients and it has functional role in the host response to COVID-19.",
keywords = "Virology, human metabolism",
author = "Kleeman, \{Sam O\} and Mattia Cordioli and Timmers, \{Paul R H J\} and Atlas Khan and Pinkus Tober-Lau and Florian Kurth and Vadim Demichev and Meyer, \{Hannah V\} and Wilson, \{James F\} and Markus Ralser and Krzysztof Kiryluk and Andrea Ganna and Kenneth Baillie and Tobias Janowitz",
note = "Funding Information: We thank all patients and their families who have volunteered to participate in clinical research, without whom this study would not have been possible. This work was conducted using the UK Biobank resource under application numbers 58510, 19655, and 41849. The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and the following industry partners: AbbVie Inc. AstraZeneca UK Ltd, Biogen MA Inc. Bristol Myers Squibb (and Celgene Corporation \& Celgene International II S{\`a}rl), Genentech Inc. Merck Sharp \& Dohme Corp, Pfizer Inc. GlaxoSmithKline Intellectual Property Development Ltd. Sanofi US Services Inc. Maze Therapeutics Inc. Janssen Biotech Inc, Novartis AG, and Boehringer Ingelheim. Following biobanks are acknowledged for delivering biobank samples to FinnGen: Auria Biobank (www.auria.fi/biopankki), THL Biobank (www.thl.fi/biobank), Helsinki Biobank (www.helsinginbiopankki.fi), Biobank Borealis of Northern Finland (https://www.ppshp.fi/Tutkimus-ja-opetus/Biopankki/Pages/Biobank-Borealis-briefly-in-English.aspx), Finnish Clinical Biobank Tampere (www.tays.fi/en-US/Research\_and\_development/Finnish\_Clinical\_Biobank\_Tampere), Biobank of Eastern Finland (www.ita-suomenbiopankki.fi/en), Central Finland Biobank (www.ksshp.fi/fi-FI/Potilaalle/Biopankki), Finnish Red Cross Blood Service Biobank (www.veripalvelu.fi/verenluovutus/biopankkitoiminta) and Terveystalo Biobank (www.terveystalo.com/fi/Yritystietoa/Terveystalo-Biopankki/Biopankki/). All Finnish Biobanks are members of BBMRI.fi infrastructure (www.bbmri.fi). Finnish Biobank Cooperative -FINBB (https://finbb.fi/) is the coordinator of BBMRI-ERIC operations in Finland. The Finnish biobank data can be accessed through the Fingenious services (https://site.fingenious.fi/en/) managed by FINBB. The Columbia University Biobank was supported by the Vagelos College of Physicians \& Surgeons as well as the Precision Medicine Resource and Biomedical Informatics Resource of Irving Institute for Clinical and Translational Research, home of the Columbia University's Clinical and Translational Science Award (CTSA), funded by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number UL1TR001873. The genotyping was made possible by the Columbia University Biobank and its COVID-19 Genomics Workgroup members, including Andrea Califano, Wendy Chung, Christine K. Garcia, David B. Goldstein, Iuliana Ionita-Laza, Krzysztof Kiryluk, Richard Mayeux, Sheila M. O'Byrne, Danielle Pendrick, Muredach P. Reilly, Soumitra Sengupta, Peter Sims, and Anne-Catrin Uhlemann. The work was further supported by the German Ministry of Education and Research (BMBF), as part of the National Research Node “Mass spectrometry in Systems Medicine (MSCoreSys),” under grant agreements 031L0220 (to M.R.) and 161L0221 (to V.D.). A.K. was supported by grant no. K25 (K25DK128563) from the NIH/National Institute of Diabetes and Digestive and Kidney Diseases. TJ funding CSHL, Northwell Health, Pershing Square Foundation, and the Dr. Lee MacCormick Edwards Charitable Foundation.HVM receives funding from the Simons Center for Quantitative Biology at Cold Spring Harbor Laboratory. S.K. is supported by the Starr Centennial Scholarship at the Cold Spring Harbor Laboratory School of Biological Sciences. P.R.H.J.T. and J.F.W. acknowledge funding from the UK Medical Research Council Human Genetics Unit (grant no. MC\_UU\_00007/10). Computational analyses were performed with assistance from the US National Institutes of Health Grant S10OD028632-01. S.O.K. and T.J. conceived and designed the study. S.O.K. performed a statistical and computational analysis in the UK Biobank and Charit{\'e} Hospital cohorts. M.C. P.R.H.J.T. and A.K. performed replication statistical analyses under the supervision of J.F.W. K.K, A.G. and K.B. H.V.M. provided input for the interpretation of results and design of trans-ancestry analyses. P.R.H.J.T. and K.B. provided direction for BMI-adjusted analyses. P.T. F.K. V.D. and M.R. assisted with the analysis of the Charit{\'e} Hospital cohort. S.O.K. and T.J. wrote the article with input from all co-authors, and both had access to all summary statistics from all cohorts. All co-authors approved the final version of the article, and take full responsibility for the accuracy of data and statistical analyses. P.R.H.J.T. is a salaried employee of BioAge Labs Inc. The remaining authors declare no competing interests. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = oct,
day = "21",
doi = "10.1016/j.isci.2022.105040",
language = "English",
volume = "25",
journal = "iScience",
issn = "2589-0042",
publisher = "Cell Press",
number = "10",
}