Genetically raised levels of C-reactive protein (CRP, an inflammatory protein) are associated with protection against schizophrenia, according to a Mendelian randomization study published this week in PLOS Medicine. The study, published by Behrooz Z. Alizadeh of the University Medical Centre Groningen, The Netherlands, and colleagues, found a lack of association between CRP and a number of somatic and psychiatric disorders, suggesting that many disease-associated rises in CRP levels might be a response rather than cause of the disease.
Observational studies have shown that increased blood levels of CRP are associated with certain diseases, suggesting these diseases might be controlled with drugs that reduce CRP levels. Alizadeh and colleagues undertook a Mendelian randomization study, using genetic variants that affect CRP levels to determine if elevated CRP has a genetically predictable, causal relationship with 32 common complex disorders. The researchers report that genetically increased CRP was significantly associated with a reduced risk of schizophrenia (for 10% increased CRP, odds ratio [OR] 0.86 [95% CI 0.79-0.94]; p < 0.001). In addition, they found nominally significant associations (which remain to be confirmed) between genetically increased CRP levels and increased risk of arthritis, elevated serum albumin, raised blood pressure, and bipolar disorder. There was no evidence for an effect of genetically increased CRP levels on any of the other 27 outcomes studied.
Though this is one the largest studies on the topic, the reliability of these findings depends on the validity of the assumptions of Mendelian randomization, including the ability of the genetic scores to explain variations in CRP level. However, these findings suggest that interventions designed to lower CRP level are unlikely to decrease the risk of people developing the majority of common complex somatic and neuropsychiatric outcomes.
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Research Article
Funding
Please refer to file S1 Financial Disclosure for full information with regard to funding and financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests
The authors have declared that no competing interests exist.
Citation
Prins BP, Abbasi A, Wong A, Vaez A, Nolte I, Franceschini N, et al. (2016) Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study. PLoS Med 13(6): e1001976. doi:10.1371/journal.pmed.1001976
Author Affiliations
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom
Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, United States of America
Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, United States of America
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
Center for Applied Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, United States of America
Department of Academic Rheumatology, University of Nottingham, Nottingham, United Kingdom
Department of Molecular Neuroscience, Institute of Neurology, London, United Kingdom
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
Neurology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
Division of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, United States of America
Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
McKusick-Nathans Institute of Genetic Medicine and Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
NHLBI's Framingham Heart Study, Center for Population Studies and Harvard Medical School, Framingham, Massachusetts, United States of America
Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
NIHR Barts Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, United Kingdom
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
Partners HealthCare Center for Personalized Genetic Medicine, Boston, Massachusetts, United States of America
Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom
Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
Endocrine Genetics Research Institute, McGill University Health Center, Montreal, Quebec, Canada
Department of Rheumatology & Clinical Immunology and Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands
Complex Disease Genetics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America
Department of Epidemiology, Erasmus University Rotterdam, University Medical Centre Rotterdam, Rotterdam, the Netherlands
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
Complex Genetic Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom
Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
Cardiogenetics Lab, Cardiovascular and Cell Sciences Institute, St George's Hospital Medical School, London, United Kingdom
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Contact:
Behrooz Z. Alizadeh MD, MSc, PhD
Unit of Digestive System Diseases,
University of Groningen, University Medical Center Groningen
Department of Epidemiology
Hanzeplein 1
Post Box 30 001
Groningen, 9700 RB
NETHERLANDS
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+31 50 36 10738 (secretary)
FAX: +31 50 36 14493
b.z.alizadeh@umcg.nl
Journal
PLoS Medicine