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dc.contributor.authorWang, Xiaoliang
dc.contributor.authorDai, James Y
dc.contributor.authorAlbanes, Demetrius
dc.contributor.authorArndt, Volker
dc.contributor.authorBerndt, Sonja I
dc.contributor.authorBézieau, Stéphane
dc.contributor.authorBrenner, Hermann
dc.contributor.authorBuchanan, Daniel D
dc.contributor.authorButterbach, Katja
dc.contributor.authorCaan, Bette
dc.contributor.authorCasey, Graham
dc.contributor.authorCampbell, Peter T
dc.contributor.authorChan, Andrew T
dc.contributor.authorChen, Zhengyi
dc.contributor.authorChang-Claude, Jenny
dc.contributor.authorCotterchio, Michelle
dc.contributor.authorEaston, Douglas
dc.contributor.authorGiles, Graham G
dc.contributor.authorGiovannucci, Edward
dc.contributor.authorGrady, William M
dc.contributor.authorHoffmeister, Michael
dc.contributor.authorHopper, John L
dc.contributor.authorHsu, Li
dc.contributor.authorJenkins, Mark A
dc.contributor.authorJoshi, Amit D
dc.contributor.authorLampe, Johanna W
dc.contributor.authorLarsson, Susanna C
dc.contributor.authorLejbkowicz, Flavio
dc.contributor.authorLi, Li
dc.contributor.authorLindblom, Annika
dc.contributor.authorLe Marchand, Loic
dc.contributor.authorMartin, Vicente
dc.contributor.authorMilne, Roger L
dc.contributor.authorMoreno, Victor
dc.contributor.authorNewcomb, Polly A
dc.contributor.authorOffitt, Kenneth
dc.contributor.authorOgino, Shuji
dc.contributor.authorPharoah, Paul
dc.contributor.authorPinchev, Mila
dc.contributor.authorPotter, John D
dc.contributor.authorRennert, Hedy S
dc.contributor.authorRennert, Gad
dc.contributor.authorSaliba, Walid
dc.contributor.authorSchafmayer, Clemens
dc.contributor.authorSchoen, Robert E
dc.contributor.authorSchrotz-King, Petra
dc.contributor.authorSlattery, Martha L
dc.contributor.authorSong, Mingyang
dc.contributor.authorStegmaier, Christa
dc.contributor.authorWeinstein, Stephanie J
dc.contributor.authorWolk, Alicja
dc.contributor.authorWoods, Michael O
dc.contributor.authorWu, Anna H
dc.contributor.authorGruber, Stephen B
dc.contributor.authorPeters, Ulrike
dc.contributor.authorWhite, Emily
dc.date.accessioned2018-12-12T00:30:48Z
dc.date.available2018-12-12T00:30:48Z
dc.date.issued2019-06-01
dc.identifier.issn0300-5771
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286693
dc.description.abstractBACKGROUND: 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.
dc.description.sponsorshipGECCO (Genetics and Epidemiology of Colorectal Cancer Consortium) is supported by the National Cancer Institute (NCI), National Institutes of Health (NIH), U.S. Department of Health and Human Services (U01 CA137088; R01 CA059045; U01 CA164930). ASTERISK was funded by a Hospital Clinical Research Program (PHRC-BRD09/C) from the University Hospital Center of Nantes (CHU de Nantes) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte Contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC). COLO2&3 (Hawai’i Colorectal Cancer Studies 2 & 3) is supported by the NIH (R01 CA60987). DACHS (Darmkrebs: Chancen der Verhutüng durch Screening) was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1 and BR 1704/17-1), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A and 01ER1505B). DALS (Diet, Activity and Lifestyle Survey) is supported by the NIH (R01 CA48998 to P.A. Slattery). HPFS (Health Professionals Follow-up Study) is supported by the NIH (P01 CA055075, UM1 CA167552, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003), NHS (Nurses’ Health Study) by the NIH (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003) and PHS (Physician’s Health Study) by the NIH (R01 CA042182). MEC (Multiethnic Cohort Study) is supported by the NIH (R37 CA54281, P01 CA033619, and R01 CA63464). OFCCR (the Ontario Registry for Studies of Familial Colorectal Cancer) was supported by NIH (U01 CA074783; see CCFR section above), and additional funding toward genetic analyses of OFCCR was supported by a GL2 grant from the Ontario Research Fund, Canadian Institutes of Health Research and a Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. PLCO (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial) is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. PMH-CCFR (Postmenopausal Hormone Study-Colon Cancer Family Registry) is supported by the NIH (R01 CA076366 to P.A. Newcomb). VITAL (VITamins And Lifestyle) is supported by the NIH (K05 CA154337 to E.White). WHI (Women’s Health Initiative) is supported by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. X.Wang and E. White were also supported by the NCI (R25 CA094880). CORECT (the Colorectal Transdisciplinary Study) is supported by the NCI under RFA # CA-09-002 as part of the GAME-ON consortium (US NIH, U19 CA148107) with additional support from the NCI grants (R01 CA81488 and P30 CA14089), the National Human Genome Research Institute at the US NIH (T32 HG000040) and the National Institute of Environmental Health Sciences at the US NIH (T32 ES013678). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in CORECT, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or CORECT. CCFR (the Colon Cancer Family Registry) is supported by grant UM1 CA167551 from the US NCI and through cooperative agreements with members of the CCFR and principal investigators of the Australasian Colorectal Cancer Family Registry (US NIH, U01 CA074778 and U01/U24 CA097735), University of South California Consortium Colorectal Cancer Family Registry for Colon Cancer Studies (US NIH, U01/U24 CA074799), the Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (US NIH, U01/U24 CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (US NIH, U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (US NIH, U01/U24 CA074794), and the University of Hawaii Colorectal Cancer Family Registry (US NIH, U01/U24 CA074806). The Colon CFR Illumina GWAS was supported by NCI/NIH grant U01 CA122839 and R01 CA143237 to G Casey. CPSII (the Cancer Prevention Study-II Nutrition Cohort) is funded by the American Cancer Society. MECC was supported by the NIH, U.S. Department of Health and Human Services (R01 CA81488 to SB Gruber and G Rennert). The MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria, GALEON: FIS Intrasalud (PI13/01136). The MCCS was further supported by Australian NHMRC grants 509348, 209057, 251553 and 504711, and by infrastructure provided by Cancer Council Victoria. The NFCCR (Newfoundland Colorectal Cancer Registry) was supported by an Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research (CRT 43821); the NIH, U.S. Department of Health and Human Serivces (U01 CA74783); and National Cancer Institute of Canada grants (18223 and 18226). The Kentucky study was supported by the US NCI R01 CA136726, and the Clinical Investigator Award from Damon Runyon Cancer Research Foundation (CI-8). The Spain study was supported by Instituto de Salud Carlos III, co-funded by FEDER funds –a way to build Europe– grants PI14-613 and PI09-1286. SEARCH was supported by the Cancer Research UK (C490/A16561). The Sweden-Wolk was supported by grants from the Swedish Research Council/Infrastructure grant, the Swedish Cancer Foundation and Karolinska Institute’s Distinguished Professor Award to Alicja Wolk. The ATBC Study is supported by the Intramural Research Program of the U.S. NCI and by U.S. Public Health Service contract HHSN261201500005C from the NCI, Department of Health and Human Services. The ColoCare-heidelberg and the ColoCare-Seattle studies were funded by the US NIH (grants 2P30CA015704-40, R01 CA189184 and U01 CA152756), the Matthias Lackas-Foundation, the German Consortium for Translational Cancer Research, and the EU TRANSCAN initiative. ESTER_VERDI was supported by grants from the Baden-Wϋrttemberg Ministry of Science. The work at MSKCC (Memorial Sloan Kettering Cancer Center in New York) was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation. D. Buchanan is also supported by University of Melbourne Research at Melbourne Accelerator Program (R@MAP) and NHMRC R.D. Wright Career Development Fellowship. Dr. M. Song was supported by the American Cancer Society (Grant number MRSG-17-220-01 – NEC to M.S.); by the 2017 AACR-AstraZeneca Fellowship in Immuno-oncology Research (Grant Number 17-40-12-SONG to M.S.); by the U.S. National Institutes of Health (NIH) grants [K99 CA215314 to M.S.].
dc.format.mediumPrint
dc.languageeng
dc.publisherOxford University Press (OUP)
dc.subjectHumans
dc.subjectColorectal Neoplasms
dc.subjectGenetic Predisposition to Disease
dc.subjectC-Reactive Protein
dc.subjectLogistic Models
dc.subjectCausality
dc.subjectPolymorphism, Single Nucleotide
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectMendelian Randomization Analysis
dc.titleMendelian randomization analysis of C-reactive protein on colorectal cancer risk.
dc.typeArticle
prism.endingPage780
prism.issueIdentifier3
prism.publicationDate2019
prism.publicationNameInt J Epidemiol
prism.startingPage767
prism.volume48
dc.identifier.doi10.17863/CAM.34000
dcterms.dateAccepted2018-10-15
rioxxterms.versionofrecord10.1093/ije/dyy244
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2019-06
dc.contributor.orcidEaston, Douglas [0000-0003-2444-3247]
dc.contributor.orcidPharoah, Paul [0000-0001-8494-732X]
dc.identifier.eissn1464-3685
rioxxterms.typeJournal Article/Review
cam.issuedOnline2018-11-21
rioxxterms.freetoread.startdate2019-11-21


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