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European Journal of Epidemiology

, Volume 32, Issue 5, pp 419–430 | Cite as

Genetic variation in the ADIPOQ gene, adiponectin concentrations and risk of colorectal cancer: a Mendelian Randomization analysis using data from three large cohort studies

  • Katharina NimptschEmail author
  • Mingyang Song
  • Krasimira Aleksandrova
  • Michail Katsoulis
  • Heinz Freisling
  • Mazda Jenab
  • Marc J. Gunter
  • Konstantinos K. Tsilidis
  • Elisabete Weiderpass
  • H. Bas Bueno-De-Mesquita
  • Dawn Q. Chong
  • Majken K. Jensen
  • Chunsen Wu
  • Kim Overvad
  • Tilman Kühn
  • Myrto Barrdahl
  • Olle Melander
  • Karin Jirström
  • Petra H. Peeters
  • Sabina Sieri
  • Salvatore Panico
  • Amanda J. Cross
  • Elio Riboli
  • Bethany Van Guelpen
  • Robin Myte
  • José María Huerta
  • Miguel Rodriguez-Barranco
  • José Ramón Quirós
  • Miren Dorronsoro
  • Anne Tjønneland
  • Anja Olsen
  • Ruth Travis
  • Marie-Christine Boutron-Ruault
  • Franck Carbonnel
  • Gianluca Severi
  • Catalina Bonet
  • Domenico Palli
  • Jürgen Janke
  • Young-Ae Lee
  • Heiner Boeing
  • Edward L. Giovannucci
  • Shuji Ogino
  • Charles S. Fuchs
  • Eric Rimm
  • Kana Wu
  • Andrew T. Chan
  • Tobias Pischon
CANCER

Abstract

Higher levels of circulating adiponectin have been related to lower risk of colorectal cancer in several prospective cohort studies, but it remains unclear whether this association may be causal. We aimed to improve causal inference in a Mendelian Randomization meta-analysis using nested case–control studies of the European Prospective Investigation into Cancer and Nutrition (EPIC, 623 cases, 623 matched controls), the Health Professionals Follow-up Study (HPFS, 231 cases, 230 controls) and the Nurses’ Health Study (NHS, 399 cases, 774 controls) with available data on pre-diagnostic adiponectin concentrations and selected single nucleotide polymorphisms in the ADIPOQ gene. We created an ADIPOQ allele score that explained approximately 3% of the interindividual variation in adiponectin concentrations. The ADIPOQ allele score was not associated with risk of colorectal cancer in logistic regression analyses (pooled OR per score-unit unit 0.97, 95% CI 0.91, 1.04). Genetically determined twofold higher adiponectin was not significantly associated with risk of colorectal cancer using the ADIPOQ allele score as instrumental variable (pooled OR 0.73, 95% CI 0.40, 1.34). In a summary instrumental variable analysis (based on previously published data) with higher statistical power, no association between genetically determined twofold higher adiponectin and risk of colorectal cancer was observed (0.99, 95% CI 0.93, 1.06 in women and 0.94, 95% CI 0.88, 1.01 in men). Thus, our study does not support a causal effect of circulating adiponectin on colorectal cancer risk. Due to the limited genetic determination of adiponectin, larger Mendelian Randomization studies are necessary to clarify whether adiponectin is causally related to lower risk of colorectal cancer.

Keywords

Adiponectin ADIPOQ Colorectal cancer Mendelian Randomization 

Notes

Acknowledgements

The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence Programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI13/00061 to Granada; PI13/01162 to EPIC-Murcia), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (No. 6236), and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). Measurement of biomarkers in EPIC was partly supported by World Cancer Research Fund International and Wereld Kanker Onderzoek Fonds (WCRF NL). The research based on the Nurses’ Health Study and the Health Professional Follow-up Study are financially supported by U.S. NIH grants [P01 CA87969, UM1 CA186107, R01 CA49449 (to NHS), P01 CA55075, UM1 CA167552 (to HPFS), P50 CA127003 (to C.S. Fuchs), R01 CA151993, R35 CA197735 (to S. Ogino), K24 DK098311 and R01 CA137178 (to A.T. Chan)]. A.T. Chan is a Damon Runyon Clinical Investigator. We would like to thank the participants and staff of the Nurses’ Health Study and Health Professionals Follow-up Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.

Compliance with ethical standards

Conflict of interest

Andrew T. Chan declared consultancies for Bayer Healthcare and Pfizer Inc. Ruth Travis declared salary and support for EPIC-Oxford from Cancer Research UK (paid by the University of Oxford), support for prostate cancer research project on metabolomics from the World Cancer Research Fund as well as support for EPIC-Oxford from the UK Medical Research Council. All other authors declared no potential conflict of interest.

Supplementary material

10654_2017_262_MOESM1_ESM.docx (20 kb)
Supplementary material 1 (DOCX 19 kb)

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Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  • Katharina Nimptsch
    • 1
    • 2
    Email author
  • Mingyang Song
    • 2
    • 3
    • 4
    • 5
  • Krasimira Aleksandrova
    • 6
  • Michail Katsoulis
    • 7
    • 8
  • Heinz Freisling
    • 9
  • Mazda Jenab
    • 9
  • Marc J. Gunter
    • 9
  • Konstantinos K. Tsilidis
    • 10
    • 11
  • Elisabete Weiderpass
    • 12
    • 13
    • 14
    • 15
  • H. Bas Bueno-De-Mesquita
    • 10
    • 16
    • 17
  • Dawn Q. Chong
    • 4
    • 5
    • 18
  • Majken K. Jensen
    • 2
    • 19
  • Chunsen Wu
    • 20
    • 21
    • 22
  • Kim Overvad
    • 20
  • Tilman Kühn
    • 23
  • Myrto Barrdahl
    • 23
  • Olle Melander
    • 24
  • Karin Jirström
    • 24
  • Petra H. Peeters
    • 25
    • 26
  • Sabina Sieri
    • 27
  • Salvatore Panico
    • 28
  • Amanda J. Cross
    • 10
  • Elio Riboli
    • 10
  • Bethany Van Guelpen
    • 29
  • Robin Myte
    • 29
  • José María Huerta
    • 30
    • 31
  • Miguel Rodriguez-Barranco
    • 31
    • 32
  • José Ramón Quirós
    • 33
  • Miren Dorronsoro
    • 34
  • Anne Tjønneland
    • 35
  • Anja Olsen
    • 35
  • Ruth Travis
    • 36
  • Marie-Christine Boutron-Ruault
    • 37
    • 38
  • Franck Carbonnel
    • 37
    • 38
    • 39
  • Gianluca Severi
    • 37
    • 38
    • 40
    • 41
    • 42
  • Catalina Bonet
    • 43
  • Domenico Palli
    • 44
  • Jürgen Janke
    • 1
  • Young-Ae Lee
    • 45
  • Heiner Boeing
    • 46
  • Edward L. Giovannucci
    • 2
    • 3
    • 19
  • Shuji Ogino
    • 3
    • 19
    • 47
    • 48
  • Charles S. Fuchs
    • 19
    • 47
  • Eric Rimm
    • 2
    • 3
    • 19
  • Kana Wu
    • 2
  • Andrew T. Chan
    • 4
    • 5
    • 19
    • 49
  • Tobias Pischon
    • 1
    • 50
  1. 1.Molecular Epidemiology Research GroupMax Delbrück Center for Molecular Medicine (MDC)BerlinGermany
  2. 2.Department of NutritionHarvard T.H. Chan School of Public HealthBostonUSA
  3. 3.Department of EpidemiologyHarvard T.H. Chan School of Public HealthBostonUSA
  4. 4.Division of GastroenterologyMassachusetts General Hospital and Harvard Medical SchoolBostonUSA
  5. 5.Clinical and Translational Epidemiology UnitMassachusetts General Hospital and Harvard Medical SchoolBostonUSA
  6. 6.Nutrition, Immunity and Metabolism Start-up Lab, Department of EpidemiologyGerman Institute of Human Nutrition (DIfE), Potsdam-RehbrueckeNuthetalGermany
  7. 7.Hellenic Health FoundationAthensGreece
  8. 8.Farr Institute of Health Informatics Research at LondonUCLLondonUK
  9. 9.International Agency for Research on Cancer (IARC-WHO)LyonFrance
  10. 10.Department of Epidemiology and Biostatistics, The School of Public HealthImperial College LondonLondonUK
  11. 11.Department of Hygiene and EpidemiologyUniversity of Ioannina School of MedicineIoanninaGreece
  12. 12.Department of Community Medicine, Faculty of Health SciencesUniversity of Tromsø, The Arctic University of NorwayTromsøNorway
  13. 13.Department of ResearchCancer Registry of NorwayOsloNorway
  14. 14.Department of Medical Epidemiology and BiostatisticsKarolinska InstitutetStockholmSweden
  15. 15.Samfundet FolkhälsanHelsinkiFinland
  16. 16.Department for Determinants of Chronic Diseases (DCD)National Institute for Public Health and the Environment (RIVM)BilthovenThe Netherlands
  17. 17.Department of Social and Preventive Medicine, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
  18. 18.Division of Medical OncologyNational Cancer Centre SingaporeSingaporeSingapore
  19. 19.Channing Division of Network Medicine, Department of MedicineBrigham and Women’s Hospital, and Harvard Medical SchoolBostonUSA
  20. 20.Section for Epidemiology, Department of Public HealthAarhus UniversityAarhusDenmark
  21. 21.Institute of Clinical ResearchUniversity of Southern DenmarkOdenseDenmark
  22. 22.Odense University HospitalOdenseDenmark
  23. 23.Division of Cancer EpidemiologyGerman Cancer Research CenterHeidelbergGermany
  24. 24.Department of Clinical Sciences LundLund UniversityMalmöSweden
  25. 25.Department of Epidemiology, Julius Center for Health Sciences and Primary CareUniversity Medical Center UtrechtUtrechtThe Netherlands
  26. 26.MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public HealthImperial CollegeLondonUK
  27. 27.Epidemiology and Prevention UnitFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
  28. 28.Dipartimento di Medicina Clinica e ChirurgiaFederico II UniversityNaplesItaly
  29. 29.Department of Radiation Sciences, OncologyUmeå UniversityUmeåSweden
  30. 30.Department of EpidemiologyMurcia Regional Health Council, IMIB-ArrixacaMurciaSpain
  31. 31.CIBER Epidemiología y Salud Pública (CIBERESP)MadridSpain
  32. 32.Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs, GRANADAHospitales Universitarios de Granada/Universidad de GranadaGranadaSpain
  33. 33.Public Health DirectorateAsturiasSpain
  34. 34.Public Health Direction and Biodonostia Research Institute- CiberespBasque Regional Health DepartmentSan SebastianSpain
  35. 35.Danish Cancer Society Research CenterCopenhagenDenmark
  36. 36.Cancer Epidemiology Unit, Nuffield Department of Population HealthUniversity of OxfordOxfordUK
  37. 37.Université Paris-Sud, UVSQ, CESP, INSERMUniversité Paris-SaclayVillejuifFrance
  38. 38.Gustave RoussyVillejuifFrance
  39. 39.Department of Gastroenterology, Assistance Publique-Hôpitaux de Paris (AP-HP), University hospitals Paris-Sud, Site de BicêtreParis Sud University, Paris XIVillejuifFrance
  40. 40.Human Genetics Foundation (HuGeF)TurinItaly
  41. 41.Cancer Council VictoriaMelbourneAustralia
  42. 42.University of MelbourneMelbourneAustralia
  43. 43.Unit of Nutrition and Cancer, Cancer Epidemiology Research ProgrammeCatalan Institute of Oncology (ICO)BarcelonaSpain
  44. 44.Cancer Research and Prevention Institute (ISPO)FlorenceItaly
  45. 45.Genetics of Allergic Disease Research GroupMax Delbrück Center for Molecular Medicine (MDC)BerlinGermany
  46. 46.Department of EpidemiologyGerman Institute of Human Nutrition (DIfE), Potsdam-RehbrueckeNuthetalGermany
  47. 47.Department of Medical OncologyDana-Farber Cancer Institute and Harvard Medical SchoolBostonUSA
  48. 48.Division of MPE Molecular Pathological Epidemiology, Department of PathologyBrigham and Women’s Hospital, and Harvard Medical SchoolBostonUSA
  49. 49.Broad InstituteCambridgeUSA
  50. 50.Charité UniversitätsmedizinBerlinGermany

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