Global assessment of C-reactive protein and health-related outcomes: an umbrella review of evidence from observational s
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REVIEW
Global assessment of C‑reactive protein and health‑related outcomes: an umbrella review of evidence from observational studies and Mendelian randomization studies Georgios Markozannes1 · Charalampia Koutsioumpa1,2,3 · Sofia Cividini4 · Grace Monori5 · Konstantinos K. Tsilidis1,5 · Nikolaos Kretsavos1 · Evropi Theodoratou6,7 · Dipender Gill5 · John PA Ioannidis8,9,10,11,12 · Ioanna Tzoulaki1,5 Received: 3 December 2019 / Accepted: 25 August 2020 © The Author(s) 2020
Abstract C-reactive protein (CRP) has been studied extensively for association with a large number of non-infectious diseases and outcomes. We aimed to evaluate the breadth and validity of associations between CRP and non-infectious, chronic health outcomes and biomarkers. We conducted an umbrella review of systematic reviews and meta-analyses and a systematic review of Mendelian randomization (MR) studies. PubMed, Scopus, and Cochrane Database of Systematic Reviews were systematically searched from inception up to March 2019. Meta-analyses of observational studies and MR studies examining associations between CRP and health outcomes were identified, excluding studies on the diagnostic value of CRP for infections. We found 113 meta-analytic comparisons of observational studies and 196 MR analyses, covering a wide range of outcomes. The overwhelming majority of the meta-analyses of observational studies reported a nominally statistically significant result (95/113, 84.1%); however, the majority of the meta-analyses displayed substantial heterogeneity (47.8%), small study effects (39.8%) or excess significance (41.6%). Only two outcomes, cardiovascular mortality and venous thromboembolism, showed convincing evidence of association with CRP levels. When examining the MR literature, we found MR studies for 53/113 outcomes examined in the observational study meta-analyses but substantial support for a causal association with CRP was not observed for any phenotype. Despite the striking amount of research on CRP, convincing evidence for associations and causal effects is remarkably limited. Keywords Umbrella review · Meta-analysis · Systematic review · C-reactive protein · CRP · Mendelian randomization · Bias Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10654-020-00681-w) contains supplementary material, which is available to authorized users. * Ioanna Tzoulaki [email protected] 1
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Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
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Department of Medicine, Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA 94305, USA
Department of Hygiene and Epidemiology, University of Ioannina Medical School, 45110 Ioannina, Greece
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Department of Neurobiology, Harvard Medical School, Boston, MA, USA
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3
BBS Program, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA
Department of Health Research and Policy, Stanford University School of Medicine, Stanford
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