Mendelian Randomization of Circulating Polyunsaturated Fatty Acids and Colorectal Cancer Risk

Nikhil K Khankari¹, Barbara L Banbury², Maria C Borges^{3

4}, Philip Haycock^{3

4}, Demetrius Albanes⁵, Volker Arndt⁶, Sonja I Berndt⁵, Stéphane Bézieau⁷, Hermann Brenner^{6

8

9}, Peter T Campbell¹⁰, Graham Casey¹¹, Andrew T Chan^{12

13

14

15

16

17}, Jenny Chang-Claude^{18

19}, David V Conti²⁰, Michelle Cotterchio²¹, Dallas R English^{22

23}, Jane C Figueiredo^{20

24}, Graham G Giles^{22

23}, Edward L Giovannucci^{13

16

25}, Marc J Gunter²⁶, Jochen Hampe²⁷, Michael Hoffmeister⁶, John L Hopper²², Mark A Jenkins²², Amit D Joshi^{14

16}, Loic Le Marchand²⁸, Mathieu Lemire²⁹, Christopher I Li², Li Li³⁰, Annika Lindblom^{31

32}, Vicente Martín³³, Victor Moreno^{34

35

36}, Polly A Newcomb^{2

37}, Kenneth Offit^{38

39}, Paul D P Pharoah⁴⁰, Gad Rennert^{41

42

43}, Lori C Sakoda^{2

44}, Clemens Schafmayer⁴⁵, Stephanie L Schmit^{20

46}, Martha L Slattery⁴⁷, Mingyang Song^{12

14

16

25}, Stephen N Thibodeau⁴⁸, Cornelia M Ulrich⁴⁹, Stephanie J Weinstein⁵, Emily White^{2

37}, Aung Ko Win²², Alicja Wolk⁵⁰, Michael O Woods⁵¹, Anna H Wu²⁰, Qiuyin Cai⁵², Joshua C Denny^{53

54}, Todd L Edwards^{52

53}, Harvey J Murff⁵², Stephen B Gruber⁵⁵, Ulrike Peters^{2

37}, Wei Zheng⁵²

Affiliations

¹ Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. nikhil.khankari@vumc.org.
² Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
³ Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
⁴ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
⁵ Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.
⁶ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷ Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
⁸ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
⁹ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁰ Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia.
¹¹ Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
¹² Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
¹³ Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
¹⁴ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
¹⁵ Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
¹⁶ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
¹⁷ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
¹⁸ University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany.
¹⁹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁰ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
²¹ Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada.
²² Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
²³ Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
²⁴ Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
²⁵ Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
²⁶ Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
²⁷ Department of Medicine, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
²⁸ University of Hawaii Cancer Center, Honolulu, Hawaii.
²⁹ PanCuRx Translational Research Initiative, Ontario, Institute for Cancer Research, Toronto, Ontario, Canada.
³⁰ Department of Family Medicine, University of Virginia, Charlottesville, Virginia.
³¹ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
³² Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
³³ Área de Medicina Preventiva y Salud Publica, Universidad de León, León, Spain.
³⁴ Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
³⁵ CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
³⁶ Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
³⁷ Department of Epidemiology, University of Washington School of Public Health and Community Medicine, Seattle, Washington.
³⁸ Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
³⁹ Department of Medicine, Weill Cornell Medical College, New York, New York.
⁴⁰ Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
⁴¹ Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
⁴² Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
⁴³ Clalit National Cancer Control Center, Haifa, Israel.
⁴⁴ Division of Research, Kaiser Permanente Northern California, Oakland, California.
⁴⁵ Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
⁴⁶ Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
⁴⁷ Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, Utah.
⁴⁸ Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
⁴⁹ Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.
⁵⁰ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁵¹ Discipline of Genetics, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
⁵² Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
⁵³ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee.
⁵⁴ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee.
⁵⁵ Department of Medical Oncology, City of Hope National Medical Center, Duarte, California.

PMID: 32051193
PMCID: PMC7125012
DOI: 10.1158/1055-9965.EPI-19-0891

Mendelian Randomization of Circulating Polyunsaturated Fatty Acids and Colorectal Cancer Risk

Nikhil K Khankari et al. Cancer Epidemiol Biomarkers Prev. 2020 Apr.

. 2020 Apr;29(4):860-870.

doi: 10.1158/1055-9965.EPI-19-0891. Epub 2020 Feb 12.

Authors

Affiliations

¹ Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. nikhil.khankari@vumc.org.
² Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
³ Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
⁴ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
⁵ Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.
⁶ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷ Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
⁸ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
⁹ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁰ Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia.
¹¹ Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
¹² Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
¹³ Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
¹⁴ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
¹⁵ Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
¹⁶ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
¹⁷ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
¹⁸ University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany.
¹⁹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁰ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
²¹ Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada.
²² Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
²³ Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
²⁴ Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
²⁵ Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
²⁶ Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
²⁷ Department of Medicine, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
²⁸ University of Hawaii Cancer Center, Honolulu, Hawaii.
²⁹ PanCuRx Translational Research Initiative, Ontario, Institute for Cancer Research, Toronto, Ontario, Canada.
³⁰ Department of Family Medicine, University of Virginia, Charlottesville, Virginia.
³¹ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
³² Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
³³ Área de Medicina Preventiva y Salud Publica, Universidad de León, León, Spain.
³⁴ Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
³⁵ CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
³⁶ Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
³⁷ Department of Epidemiology, University of Washington School of Public Health and Community Medicine, Seattle, Washington.
³⁸ Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
³⁹ Department of Medicine, Weill Cornell Medical College, New York, New York.
⁴⁰ Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
⁴¹ Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
⁴² Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
⁴³ Clalit National Cancer Control Center, Haifa, Israel.
⁴⁴ Division of Research, Kaiser Permanente Northern California, Oakland, California.
⁴⁵ Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
⁴⁶ Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
⁴⁷ Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, Utah.
⁴⁸ Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
⁴⁹ Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.
⁵⁰ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁵¹ Discipline of Genetics, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
⁵² Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
⁵³ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee.
⁵⁴ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee.
⁵⁵ Department of Medical Oncology, City of Hope National Medical Center, Duarte, California.

PMID: 32051193
PMCID: PMC7125012
DOI: 10.1158/1055-9965.EPI-19-0891

Abstract

Background: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk.

Methods: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined.

Results: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [OR_LA = 0.96; 95% confidence interval (CI) = 0.93-0.98; P = 5.2 × 10^-4] and α-linolenic acid (OR_ALA = 0.95; 95% CI = 0.92-0.97; P = 5.4 × 10^-5), whereas modest increased risks were observed for arachidonic (OR_AA = 1.06; 95% CI = 1.03-1.08; P = 3.3 × 10^-5), eicosapentaenoic (OR_EPA = 1.04; 95% CI = 1.01-1.07; P = 2.5 × 10^-3), and docosapentaenoic acids (OR_DPA = 1.03; 95% CI = 1.01-1.06; P = 1.2 × 10^-2). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses.

Conclusions: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk.

Impact: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.

PubMed Disclaimer

Conflict of interest statement

CONFLICTS OF INTEREST:

The authors declare no potential conflicts of interest.

References

1. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87–108. doi:10.3322/caac.21262 - DOI - PubMed
1. Lippi G, Mattiuzzi C, Cervellin G. Meat consumption and cancer risk: a critical review of published meta-analyses. Crit Rev Oncol Hematol 2016;97:1–14. doi:10.1016/j.critrevonc.2015.11.008 - DOI - PubMed
1. Theodoratou E, Timofeeva M, Li X, et al. Nature, Nurture, and Cancer Risks: Genetic and Nutritional Contributions to Cancer. Annu Rev Nutr 2017;37:293–320. doi:10.1146/annurev-nutr-071715-051004 - DOI - PMC - PubMed
1. Wang D, DuBois RN. An inflammatory mediator, prostaglandin E2, in colorectal cancer. Cancer J Sudbury Mass 2013;19:502–10. doi:10.1097/PPO.0000000000000003 - DOI - PMC - PubMed
1. Kawamori T. Enhancement of colon carcinogenesis by prostaglandin E2 administration. Carcinogenesis 2003;24:985–90. doi:10.1093/carcin/bgg033 - DOI - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
- Europe PubMed Central
- PubMed Central
Medical
- ClinicalTrials.gov
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Mendelian Randomization of Circulating Polyunsaturated Fatty Acids and Colorectal Cancer Risk

Affiliations

Mendelian Randomization of Circulating Polyunsaturated Fatty Acids and Colorectal Cancer Risk

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical