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Mendelian randomization analysis of C-reactive protein on colorectal cancer risk.
Pubmed ID
30476131 (View this publication on the PubMed website)
Digital Object Identifier
Int J Epidemiol. 2019 Jun 1; Volume 48 (Issue 3): Pages 767-780
Wang X, Dai JY, Albanes D, Arndt V, Berndt SI, Bézieau S, Brenner H, Buchanan DD, Butterbach K, Caan B, Casey G, Campbell PT, Chan AT, Chen Z, Chang-Claude J, Cotterchio M, Easton DF, Giles GG, Giovannucci E, Grady WM, more Hoffmeister M, Hopper JL, Hsu L, Jenkins MA, Joshi AD, Lampe JW, Larsson SC, Lejbkowicz F, Li L, Lindblom A, Le Marchand L, Martin V, Milne RL, Moreno V, Newcomb PA, Offitt K, Ogino S, Pharoah PDP, Pinchev M, Potter JD, Rennert HS, Rennert G, Saliba W, Schafmayer C, Schoen RE, Schrotz-King P, Slattery ML, Song M, Stegmaier C, Weinstein SJ, Wolk A, Woods MO, Wu AH, Gruber SB, Peters U, White E
  • Department of Epidemiology, University of Washington, Seattle, WA, USA.
  • Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Division of Cancer Epidemiology and Genetics, US National Cancer Institute, Rockville, MD, USA.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Service de Génétique Médicale, CHU Nantes, Nantes, France.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health.
  • Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
  • Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA, USA.
  • Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
  • Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA. more
  • Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
  • Department of Family Medicine and Community Health, Mary Ann Swetland Center for Environmental Health, Case Western Reserve University, Cleveland, OH, USA.
  • Prevention and Cancer Control, Cancer Care Ontario, Toronto, ON, Canada.
  • Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
  • Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, VIC, Australia.
  • Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Department of Community Medicine and Epidemiology, Carmel Medical Center, B. Rappaport Faculty of Medicine, Technion, Haifa, Israel.
  • Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
  • Research Group on Gene-Environment Interactions and Health (GIIGAS), University of León and CIBERESP, León, Spain.
  • Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO), IDIBELL, CIBERESP, Barcelona, Spain.
  • Department of Cancer Biology and Genetics, Clinical Genetics Service, New York, NY, USA.
  • Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
  • Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA.
  • Saarland Cancer Registry, Saarland, Germany.
  • Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
  • Victorian Comprehensive Cancer Centre, University of Melbourne, Parkville, VIC, Australia.
  • University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.

BACKGROUND: Chronic inflammation is a risk factor for colorectal cancer (CRC). Circulating C-reactive protein (CRP) is also moderately associated with CRC risk. However, observational studies are susceptible to unmeasured confounding or reverse causality. Using genetic risk variants as instrumental variables, we investigated the causal relationship between genetically elevated CRP concentration and CRC risk, using a Mendelian randomization approach.

METHODS: Individual-level data from 30 480 CRC cases and 22 844 controls from 33 participating studies in three international consortia were used: the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT) and the Colon Cancer Family Registry (CCFR). As instrumental variables, we included 19 single nucleotide polymorphisms (SNPs) previously associated with CRP concentration. The SNP-CRC associations were estimated using a logistic regression model adjusted for age, sex, principal components and genotyping phases. An inverse-variance weighted method was applied to estimate the causal effect of CRP on CRC risk.

RESULTS: Among the 19 CRP-associated SNPs, rs1260326 and rs6734238 were significantly associated with CRC risk (P = 7.5 × 10-4, and P = 0.003, respectively). A genetically predicted one-unit increase in the log-transformed CRP concentrations (mg/l) was not associated with increased risk of CRC [odds ratio (OR) = 1.04; 95% confidence interval (CI): 0.97, 1.12; P = 0.256). No evidence of association was observed in subgroup analyses stratified by other risk factors.

CONCLUSIONS: In spite of adequate statistical power to detect moderate association, we found genetically elevated CRP concentration was not associated with increased risk of CRC among individuals of European ancestry. Our findings suggested that circulating CRP is unlikely to be a causal factor in CRC development.

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