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Elevated CRP may be response, not cause of disease

PLOS

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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http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001976

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
+31 50 36 11987 (direct)
+31 50 36 10738 (secretary)
FAX: +31 50 36 14493
b.z.alizadeh@umcg.nl

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