Mendelian randomization of circulating polyunsaturated fatty acids and colorectal cancer risk

Nikhil K. Khankari; Barbara L. Banbury; Maria C. Borges; Philip Haycock; Demetrius Albanes; Volker Arndt; Sonja I. Berndt; Stéphane Bézieau; Brenner Hermann Brenner; Peter T. Campbell; Graham Casey; Andrew T. Chan; Jenny Chang-Claude; David V. Conti; Michelle Cotterchio; Dallas R. English; Jane C. Figueiredo; Graham G. Giles; Edward L. Giovannucci; Marc J. Gunter; Jochen Hampe; Michael Hoffmeister; John L. Hopper; Mark A. Jenkins; Amit D. Joshi; Loic Le Marchand; Mathieu Lemire; Christopher I. Li; Li Li; Annika Lindblom; Vicente Martín; Victor Moreno; Polly A. Newcomb; Kenneth Offit; Paul D.P. Pharoah; Gad Rennert; Lori C. Sakoda; Clemens Schafmayer; Stephanie L. Schmit; Martha L. Slattery; Mingyang Song; Stephen N. Thibodeau; Cornelia M. Ulrich; Stephanie J. Weinstein; Emily White; Aung Ko Win; Alicja Wolk; Michael O. Woods; Anna H. Wu; Qiuyin Cai; Joshua C. Denny; Todd L. Edwards; Harvey J. Murff; Stephen B. Gruber; Ulrike Peters; Wei Zheng

doi:10.1158/1055-9965.EPI-19-0891

Mendelian randomization of circulating polyunsaturated fatty acids and colorectal cancer risk

Nikhil K. Khankari, Barbara L. Banbury, Maria C. Borges, Philip Haycock, Demetrius Albanes, Volker Arndt, Sonja I. Berndt, Stéphane Bézieau, Brenner Hermann Brenner, Peter T. Campbell, Graham Casey, Andrew T. Chan, Jenny Chang-Claude, David V. Conti, Michelle Cotterchio, Dallas R. English, Jane C. Figueiredo, Graham G. Giles, Edward L. Giovannucci, Marc J. GunterJochen Hampe, Michael Hoffmeister, John L. Hopper, Mark A. Jenkins, Amit D. Joshi, Loic Le Marchand, Mathieu Lemire, Christopher I. Li, Li Li, Annika Lindblom, Vicente Martín, Victor Moreno, Polly A. Newcomb, Kenneth Offit, Paul D.P. Pharoah, Gad Rennert, Lori C. Sakoda, Clemens Schafmayer, Stephanie L. Schmit, Martha L. Slattery, Mingyang Song, Stephen N. Thibodeau, Cornelia M. Ulrich, Stephanie J. Weinstein, Emily White, Aung Ko Win, Alicja Wolk, Michael O. Woods, Anna H. Wu, Qiuyin Cai, Joshua C. Denny, Todd L. Edwards, Harvey J. Murff, Stephen B. Gruber, Ulrike Peters, Wei Zheng

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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 [ORLA= 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.

Original language	English (US)
Pages (from-to)	860-870
Number of pages	11
Journal	Cancer Epidemiology Biomarkers and Prevention
Volume	29
Issue number	4
DOIs	https://doi.org/10.1158/1055-9965.EPI-19-0891
State	Published - 2020
Externally published	Yes

ASJC Scopus subject areas

Medicine(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/1055-9965.EPI-19-0891

Cite this

Khankari, N. K., Banbury, B. L., Borges, M. C., Haycock, P., Albanes, D., Arndt, V., Berndt, S. I., Bézieau, S., Hermann Brenner, B., Campbell, P. T., Casey, G., Chan, A. T., Chang-Claude, J., Conti, D. V., Cotterchio, M., English, D. R., Figueiredo, J. C., Giles, G. G., Giovannucci, E. L., ... Zheng, W. (2020). Mendelian randomization of circulating polyunsaturated fatty acids and colorectal cancer risk. Cancer Epidemiology Biomarkers and Prevention, 29(4), 860-870. https://doi.org/10.1158/1055-9965.EPI-19-0891

Khankari, NK, Banbury, BL, Borges, MC, Haycock, P, Albanes, D, Arndt, V, Berndt, SI, Bézieau, S, Hermann Brenner, B, Campbell, PT, Casey, G, Chan, AT, Chang-Claude, J, Conti, DV, Cotterchio, M, English, DR, Figueiredo, JC, Giles, GG, Giovannucci, EL, Gunter, MJ, Hampe, J, Hoffmeister, M, Hopper, JL, Jenkins, MA, Joshi, AD, Le Marchand, L, Lemire, M, Li, CI, Li, L, Lindblom, A, Martín, V, Moreno, V, Newcomb, PA, Offit, K, Pharoah, PDP, Rennert, G, Sakoda, LC, Schafmayer, C, Schmit, SL, Slattery, ML, Song, M, Thibodeau, SN, Ulrich, CM, Weinstein, SJ, White, E, Win, AK, Wolk, A, Woods, MO, Wu, AH, Cai, Q, Denny, JC, Edwards, TL, Murff, HJ, Gruber, SB, Peters, U & Zheng, W 2020, 'Mendelian randomization of circulating polyunsaturated fatty acids and colorectal cancer risk', Cancer Epidemiology Biomarkers and Prevention, vol. 29, no. 4, pp. 860-870. https://doi.org/10.1158/1055-9965.EPI-19-0891

@article{43a8780b4d1349ae8ee06fb7ad2a7aa0,

title = "Mendelian randomization of circulating polyunsaturated fatty acids and colorectal cancer risk",

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 [ORLA= 0.96; 95% confidence interval (CI)= 0.93-0.98; P= 5.2 × 10-4] and α-linolenic acid (ORALA= 0.95; 95% CI= 0.92-0.97; P= 5.4 × 10-5), whereas modest increased risks were observed for arachidonic (ORAA= 1.06; 95% CI= 1.03-1.08; P= 3.3 × 10-5), eicosapentaenoic (OREPA= 1.04; 95% CI= 1.01-1.07; P= 2.5 × 10-3), and docosapentaenoic acids (ORDPA= 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.",

author = "Khankari, {Nikhil K.} and Banbury, {Barbara L.} and Borges, {Maria C.} and Philip Haycock and Demetrius Albanes and Volker Arndt and Berndt, {Sonja I.} and St{\'e}phane B{\'e}zieau and {Hermann Brenner}, Brenner and Campbell, {Peter T.} and Graham Casey and Chan, {Andrew T.} and Jenny Chang-Claude and Conti, {David V.} and Michelle Cotterchio and English, {Dallas R.} and Figueiredo, {Jane C.} and Giles, {Graham G.} and Giovannucci, {Edward L.} and Gunter, {Marc J.} and Jochen Hampe and Michael Hoffmeister and Hopper, {John L.} and Jenkins, {Mark A.} and Joshi, {Amit D.} and {Le Marchand}, Loic and Mathieu Lemire and Li, {Christopher I.} and Li Li and Annika Lindblom and Vicente Mart{\'i}n and Victor Moreno and Newcomb, {Polly A.} and Kenneth Offit and Pharoah, {Paul D.P.} and Gad Rennert and Sakoda, {Lori C.} and Clemens Schafmayer and Schmit, {Stephanie L.} and Slattery, {Martha L.} and Mingyang Song and Thibodeau, {Stephen N.} and Ulrich, {Cornelia M.} and Weinstein, {Stephanie J.} and Emily White and Win, {Aung Ko} and Alicja Wolk and Woods, {Michael O.} and Wu, {Anna H.} and Qiuyin Cai and Denny, {Joshua C.} and Edwards, {Todd L.} and Murff, {Harvey J.} and Gruber, {Stephen B.} and Ulrike Peters and Wei Zheng",

note = "Funding Information: WHI (Women's Health Initiative): The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at http:// www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI% 20Investigator%20Short%20List.pdf. The following acknowledgments are for CORECT: ColoCare: Biospecimens were provided by the ColoCare Consortium, funded by the Fred Hutchinson Cancer Research Center. Other investigators may have received specimens from the same subjects. CPS-II (American Cancer Society Cancer Prevention Study II): The authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. The authors also acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. MCCS (Melbourne Collaborative Cohort Study): This study was made possible by the contribution of many people, including the original investigators and the diligent team who recruited participants and continue to work on follow-up. The authors also are grateful to the many thousands of Melbourne residents who took part in the study and provided blood samples. SEARCH (Studies of Epidemiology and Risk Factors in Cancer Heredity): The authors acknowledge the contributions of Mitul Shah, Val Rhenius, Sue Irvine, Craig Luccarini, Patricia Harrington, Don Conroy, Rebecca Mayes, and Caroline Baynes. The Swedish Low-risk Colorectal Cancer Study: The authors thank Berith Wejderot and the Swedish Low-risk Colorectal Cancer Study group. The following funding information is for GECCO: ASTERISK: 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 Franc¸aises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne G{\'e}n{\'e}tique and the LigueR{\'e}gionaleContre le Cancer (LRCC). COLO2&3 (Hawaiian Colorectal Cancer Studies 2 and 3): NIH (R01 CA60987). CCFR: Illumina GWAS was supported by funding from the NCI, NIH (grant numbers U01 CA122839, R01 CA143247, to G. Casey). The Colon CFR/CORECT Affymetrix Axiom GWAS and OncoArray GWAS were supported by funding from NCI, NIH (grant number U19 CA148107, to S.B. Gruber). The Colon CFR participant recruitment and collection of data and biospecimens used in this study were supported by the NCI, NIH (grant number U01 CA167551) and through cooperative agreements with the following Colon CFR centers: Australasian Colorectal Cancer Family Registry (NCI/NIH grant numbers U01 CA074778 and U01/U24 CA097735), USC Consortium Colorectal Cancer Family Registry (NCI/NIH grant numbers U01/U24 CA074799), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (NCI/NIH grant number U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (NCI/NIH grant number U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074794), and University of Hawaii Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074806). Additional support for case ascertainment was provided from the Surveillance, Epidemiology and End Results (SEER) Program of the NCI to Fred Hutchinson Cancer Research Center (control nos. N01-CN-67009 and N01-PC-35142 and contract no. HHSN2612013000121), the Hawai'i Department of Health (control nos. N01-PC-67001 and N01-PC-35137 and contract no. HHSN26120100037C), and the California Department of Public Health (contracts HHSN261201000035C awarded to the University of Southern California, and the following state cancer registries: AZ, CO, MN, NC, NH, and by the Victoria Cancer Registry and Ontario Cancer Registry). DACHS: This work 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 Study): NIH (R01 CA48998, to M.L. Slattery). Harvard cohorts (HPFS, NHS, PHS): HPFS is supported by the NIH (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003), NHS by the NIH (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003), and PHS by the NIH (R01 CA042182). GECCO: NCI, NIH, U.S. Department of Health and Human Services (U01 CA164930, U01 CA137088, R01 CA059045). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. Funding Information: Funding was provided to M.O. Woods by the Canadian Cancer Society Research Institute. SEARCH: The University of Cambridge has received salary support in respect of PDPP from the NHS in the East of England through the Clinical Academic Reserve. Cancer Research UK (C490/A16561); the UK National Institute for Health Research Biomedical Research Centers at the University of Cambridge. SPAIN [The Spanish study (University Hospital of Bellvitge, L'Hospitalet, Barcelona; Hospital of Leon, Leon; Spain)]: The Spanish study was supported by Instituto de Salud Carlos III, cofunded by FEDER funds –a way to build Europe– (grants PI14-613 and PI09-1286), Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (grant 2017SGR723), and Junta de Castilla y Le{\'o}n (grant LE22A10-2). Sample collection of this work was supported by the Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d{\textquoteright}Oncolog{\'i}a de Catalunya (XBTC), Plataforma Biobancos PT13/0010/ 0013 and ICOBIOBANC, sponsored by the Catalan Institute of Oncology. Funding Information: MEC (Multiethnic Cohort): NIH (R37 CA54281, P01 CA033619, R01 CA063464, U01 CA164973). Also part of CORECT funding acknowledgments. OFCCR (Ontario Familial Colorectal Cancer Registry): NIH, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. Additional funding toward genetic analyses of OFCCR includes the Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO: 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. Funding was provided by NIH, Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIHU01 HG004446, and NIHGEI U01 HG 004438. PMH: NIH (R01 CA076366, to P.A. Newcomb). VITAL (Vitamins and Lifestyle): NIH (K05 CA154337). WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The following funding information is for studies included in CORECT: ATBC (Alpha-Tocopherol, Beta Carotene Cancer Prevention Study): The ATBC Study was supported by the U.S. Public Health Service contracts (N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C) from the National Cancer Institute. ColoCare: This work was supported by the NIH [grant numbers R01 CA189184 (to Li/C.M. Ulrich), U01 CA206110 (C.M. Ulrich/Li/Siegel/Figueireido/Colditz, 2P30CA015704-40 (Gilliland), R01 CA207371 (C.M. Ulrich/Li)], the Matthias Lackas-Foundation, the German Consortium for Translational Cancer Research, and the EU TRANSCAN initiative. CORECT Study: The CORECT Study was supported by the NCI/NIH, U.S. Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350; P01 CA196569; R01 CA201407) and National Institutes of Environmental Health Sciences, NIH (grant number T32 ES013678). CPS-II: The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study-II (CPS-II) cohort. This study was conducted with Institutional Review Board approval. ESTHER/VERDI (Epidemiologische Studie zu Chancen der Verhu€tung, Fru€her-kennung und optimierten Therapie chronischer Erkrankungen in der €alteren Bevo€lkerung; Verlauf der diagnotischen Abkl€arung bei Krebspatienten): This work was supported by grants from the Baden-Wu€rttemberg Ministry of Science, Research and Arts and the German Cancer Aid. Kentucky: This work was supported by the following: (i) Clinical Investigator Award from Damon Runyon Cancer Research Foundation (CI-8) and (ii) NCIR01CA136726; the authors acknowledge the staff at the Kentucky Cancer Registry. MCCS: Cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 509348, 209057, 251553, and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. MECC (Molecular Epidemiology of Colorectal Cancer Study): This work was supported by the NIH, U.S. Department of Health and Human Services (R01 CA81488, to S.B. Gruber and G. Rennert). MSKCC: The work at Sloan Kettering in New York was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation. Moffitt: This work was supported by funding from the NIH (grant numbers R01 CA189184, P30 CA076292), Florida Department of Health Bankhead-Coley Grant 09BN-13, and the University of South Florida Oehler Foundation. Moffitt contributions were supported in part by the Total Cancer Care Initiative, Collaborative Data Services Core, and Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, a National Cancer Institute-designated Comprehensive Cancer Center (grant number P30 CA076292). NFCCR (Newfoundland Case-Control Study): This work 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 authors acknowledge the contribution of Alexandre Belisle and the genotyping team of the McGill University and G{\'e}nome Qu{\'e}bec Innovation Centre, Montr{\'e}al, Canada, for genotyping the Sequenom panel in the NFCCR samples. Funding Information: N.K. Khankari is supported by NIH NCI K99 CA215360. M.C. Borges is supported by a Skills Development Fellowship from the UK Medical Research Council (Grant number MR/P014054/1). P.C. Haycock is supported by CRUK Population Research Postdoctoral Fellowship C52724/A20138. M. Song is supported by the American Cancer Society (grant number MRSG-17-220-01 – NEC) and the US NIH grants (K99 CA215314, R00 CA215314). The following acknowledgements are for GECCO: ASTERISK (French Association Study Evaluating Risk for Sporadic Colorectal Cancer): The authors are very grateful to Dr. Bruno Buecher, without whom this project would not have existed. They also thank all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians, and students. DACHS (Darmkrebs: Chancen der Verhu€tung durch Screening): The authors thank all participants and cooperating clinicians, and Ute Handte-Daub, Utz Bensc-heid, Muhabbet Celik, and Ursula Eilber for excellent technical assistance. Harvard cohorts: The study protocol was approved by the institutional review boards of the Brigham and Women's Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. The authors thank the participants and staff of the HPFS, NHS, and PHS 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. PLCO (Prostate, Lung, Colorectal Cancer, and Ovarian Cancer Screening Trial): The authors thank the PLCO Cancer Screening Trial screening center investigators and the staff from Information Management Services Inc and Westat Inc. Most importantly, they thank the study participants for their contributions that made this study possible. PMH (Postmenopausal Hormone study): The authors thank the study participants and staff of the Hormones and Colon Cancer study. Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",

year = "2020",

doi = "10.1158/1055-9965.EPI-19-0891",

language = "English (US)",

volume = "29",

pages = "860--870",

journal = "Cancer Epidemiology Biomarkers and Prevention",

issn = "1055-9965",

publisher = "American Association for Cancer Research Inc.",

number = "4",

}

TY - JOUR

T1 - Mendelian randomization of circulating polyunsaturated fatty acids and colorectal cancer risk

AU - Khankari, Nikhil K.

AU - Banbury, Barbara L.

AU - Borges, Maria C.

AU - Haycock, Philip

AU - Albanes, Demetrius

AU - Arndt, Volker

AU - Berndt, Sonja I.

AU - Bézieau, Stéphane

AU - Hermann Brenner, Brenner

AU - Campbell, Peter T.

AU - Casey, Graham

AU - Chan, Andrew T.

AU - Chang-Claude, Jenny

AU - Conti, David V.

AU - Cotterchio, Michelle

AU - English, Dallas R.

AU - Figueiredo, Jane C.

AU - Giles, Graham G.

AU - Giovannucci, Edward L.

AU - Gunter, Marc J.

AU - Hampe, Jochen

AU - Hoffmeister, Michael

AU - Hopper, John L.

AU - Jenkins, Mark A.

AU - Joshi, Amit D.

AU - Le Marchand, Loic

AU - Lemire, Mathieu

AU - Li, Christopher I.

AU - Li, Li

AU - Lindblom, Annika

AU - Martín, Vicente

AU - Moreno, Victor

AU - Newcomb, Polly A.

AU - Offit, Kenneth

AU - Pharoah, Paul D.P.

AU - Rennert, Gad

AU - Sakoda, Lori C.

AU - Schafmayer, Clemens

AU - Schmit, Stephanie L.

AU - Slattery, Martha L.

AU - Song, Mingyang

AU - Thibodeau, Stephen N.

AU - Ulrich, Cornelia M.

AU - Weinstein, Stephanie J.

AU - White, Emily

AU - Win, Aung Ko

AU - Wolk, Alicja

AU - Woods, Michael O.

AU - Wu, Anna H.

AU - Cai, Qiuyin

AU - Denny, Joshua C.

AU - Edwards, Todd L.

AU - Murff, Harvey J.

AU - Gruber, Stephen B.

AU - Peters, Ulrike

AU - Zheng, Wei

N1 - Funding Information: WHI (Women's Health Initiative): The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at http:// www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI% 20Investigator%20Short%20List.pdf. The following acknowledgments are for CORECT: ColoCare: Biospecimens were provided by the ColoCare Consortium, funded by the Fred Hutchinson Cancer Research Center. Other investigators may have received specimens from the same subjects. CPS-II (American Cancer Society Cancer Prevention Study II): The authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. The authors also acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. MCCS (Melbourne Collaborative Cohort Study): This study was made possible by the contribution of many people, including the original investigators and the diligent team who recruited participants and continue to work on follow-up. The authors also are grateful to the many thousands of Melbourne residents who took part in the study and provided blood samples. SEARCH (Studies of Epidemiology and Risk Factors in Cancer Heredity): The authors acknowledge the contributions of Mitul Shah, Val Rhenius, Sue Irvine, Craig Luccarini, Patricia Harrington, Don Conroy, Rebecca Mayes, and Caroline Baynes. The Swedish Low-risk Colorectal Cancer Study: The authors thank Berith Wejderot and the Swedish Low-risk Colorectal Cancer Study group. The following funding information is for GECCO: ASTERISK: 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 Franc¸aises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the LigueRégionaleContre le Cancer (LRCC). COLO2&3 (Hawaiian Colorectal Cancer Studies 2 and 3): NIH (R01 CA60987). CCFR: Illumina GWAS was supported by funding from the NCI, NIH (grant numbers U01 CA122839, R01 CA143247, to G. Casey). The Colon CFR/CORECT Affymetrix Axiom GWAS and OncoArray GWAS were supported by funding from NCI, NIH (grant number U19 CA148107, to S.B. Gruber). The Colon CFR participant recruitment and collection of data and biospecimens used in this study were supported by the NCI, NIH (grant number U01 CA167551) and through cooperative agreements with the following Colon CFR centers: Australasian Colorectal Cancer Family Registry (NCI/NIH grant numbers U01 CA074778 and U01/U24 CA097735), USC Consortium Colorectal Cancer Family Registry (NCI/NIH grant numbers U01/U24 CA074799), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (NCI/NIH grant number U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (NCI/NIH grant number U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074794), and University of Hawaii Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074806). Additional support for case ascertainment was provided from the Surveillance, Epidemiology and End Results (SEER) Program of the NCI to Fred Hutchinson Cancer Research Center (control nos. N01-CN-67009 and N01-PC-35142 and contract no. HHSN2612013000121), the Hawai'i Department of Health (control nos. N01-PC-67001 and N01-PC-35137 and contract no. HHSN26120100037C), and the California Department of Public Health (contracts HHSN261201000035C awarded to the University of Southern California, and the following state cancer registries: AZ, CO, MN, NC, NH, and by the Victoria Cancer Registry and Ontario Cancer Registry). DACHS: This work 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 Study): NIH (R01 CA48998, to M.L. Slattery). Harvard cohorts (HPFS, NHS, PHS): HPFS is supported by the NIH (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003), NHS by the NIH (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003), and PHS by the NIH (R01 CA042182). GECCO: NCI, NIH, U.S. Department of Health and Human Services (U01 CA164930, U01 CA137088, R01 CA059045). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. Funding Information: Funding was provided to M.O. Woods by the Canadian Cancer Society Research Institute. SEARCH: The University of Cambridge has received salary support in respect of PDPP from the NHS in the East of England through the Clinical Academic Reserve. Cancer Research UK (C490/A16561); the UK National Institute for Health Research Biomedical Research Centers at the University of Cambridge. SPAIN [The Spanish study (University Hospital of Bellvitge, L'Hospitalet, Barcelona; Hospital of Leon, Leon; Spain)]: The Spanish study was supported by Instituto de Salud Carlos III, cofunded by FEDER funds –a way to build Europe– (grants PI14-613 and PI09-1286), Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (grant 2017SGR723), and Junta de Castilla y León (grant LE22A10-2). Sample collection of this work was supported by the Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d’Oncología de Catalunya (XBTC), Plataforma Biobancos PT13/0010/ 0013 and ICOBIOBANC, sponsored by the Catalan Institute of Oncology. Funding Information: MEC (Multiethnic Cohort): NIH (R37 CA54281, P01 CA033619, R01 CA063464, U01 CA164973). Also part of CORECT funding acknowledgments. OFCCR (Ontario Familial Colorectal Cancer Registry): NIH, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. Additional funding toward genetic analyses of OFCCR includes the Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO: 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. Funding was provided by NIH, Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIHU01 HG004446, and NIHGEI U01 HG 004438. PMH: NIH (R01 CA076366, to P.A. Newcomb). VITAL (Vitamins and Lifestyle): NIH (K05 CA154337). WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The following funding information is for studies included in CORECT: ATBC (Alpha-Tocopherol, Beta Carotene Cancer Prevention Study): The ATBC Study was supported by the U.S. Public Health Service contracts (N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C) from the National Cancer Institute. ColoCare: This work was supported by the NIH [grant numbers R01 CA189184 (to Li/C.M. Ulrich), U01 CA206110 (C.M. Ulrich/Li/Siegel/Figueireido/Colditz, 2P30CA015704-40 (Gilliland), R01 CA207371 (C.M. Ulrich/Li)], the Matthias Lackas-Foundation, the German Consortium for Translational Cancer Research, and the EU TRANSCAN initiative. CORECT Study: The CORECT Study was supported by the NCI/NIH, U.S. Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350; P01 CA196569; R01 CA201407) and National Institutes of Environmental Health Sciences, NIH (grant number T32 ES013678). CPS-II: The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study-II (CPS-II) cohort. This study was conducted with Institutional Review Board approval. ESTHER/VERDI (Epidemiologische Studie zu Chancen der Verhu€tung, Fru€her-kennung und optimierten Therapie chronischer Erkrankungen in der €alteren Bevo€lkerung; Verlauf der diagnotischen Abkl€arung bei Krebspatienten): This work was supported by grants from the Baden-Wu€rttemberg Ministry of Science, Research and Arts and the German Cancer Aid. Kentucky: This work was supported by the following: (i) Clinical Investigator Award from Damon Runyon Cancer Research Foundation (CI-8) and (ii) NCIR01CA136726; the authors acknowledge the staff at the Kentucky Cancer Registry. MCCS: Cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 509348, 209057, 251553, and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. MECC (Molecular Epidemiology of Colorectal Cancer Study): This work was supported by the NIH, U.S. Department of Health and Human Services (R01 CA81488, to S.B. Gruber and G. Rennert). MSKCC: The work at Sloan Kettering in New York was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation. Moffitt: This work was supported by funding from the NIH (grant numbers R01 CA189184, P30 CA076292), Florida Department of Health Bankhead-Coley Grant 09BN-13, and the University of South Florida Oehler Foundation. Moffitt contributions were supported in part by the Total Cancer Care Initiative, Collaborative Data Services Core, and Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, a National Cancer Institute-designated Comprehensive Cancer Center (grant number P30 CA076292). NFCCR (Newfoundland Case-Control Study): This work 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 authors acknowledge the contribution of Alexandre Belisle and the genotyping team of the McGill University and Génome Québec Innovation Centre, Montréal, Canada, for genotyping the Sequenom panel in the NFCCR samples. Funding Information: N.K. Khankari is supported by NIH NCI K99 CA215360. M.C. Borges is supported by a Skills Development Fellowship from the UK Medical Research Council (Grant number MR/P014054/1). P.C. Haycock is supported by CRUK Population Research Postdoctoral Fellowship C52724/A20138. M. Song is supported by the American Cancer Society (grant number MRSG-17-220-01 – NEC) and the US NIH grants (K99 CA215314, R00 CA215314). The following acknowledgements are for GECCO: ASTERISK (French Association Study Evaluating Risk for Sporadic Colorectal Cancer): The authors are very grateful to Dr. Bruno Buecher, without whom this project would not have existed. They also thank all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians, and students. DACHS (Darmkrebs: Chancen der Verhu€tung durch Screening): The authors thank all participants and cooperating clinicians, and Ute Handte-Daub, Utz Bensc-heid, Muhabbet Celik, and Ursula Eilber for excellent technical assistance. Harvard cohorts: The study protocol was approved by the institutional review boards of the Brigham and Women's Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. The authors thank the participants and staff of the HPFS, NHS, and PHS 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. PLCO (Prostate, Lung, Colorectal Cancer, and Ovarian Cancer Screening Trial): The authors thank the PLCO Cancer Screening Trial screening center investigators and the staff from Information Management Services Inc and Westat Inc. Most importantly, they thank the study participants for their contributions that made this study possible. PMH (Postmenopausal Hormone study): The authors thank the study participants and staff of the Hormones and Colon Cancer study. Publisher Copyright: © 2020 American Association for Cancer Research.

PY - 2020

Y1 - 2020

N2 - 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 [ORLA= 0.96; 95% confidence interval (CI)= 0.93-0.98; P= 5.2 × 10-4] and α-linolenic acid (ORALA= 0.95; 95% CI= 0.92-0.97; P= 5.4 × 10-5), whereas modest increased risks were observed for arachidonic (ORAA= 1.06; 95% CI= 1.03-1.08; P= 3.3 × 10-5), eicosapentaenoic (OREPA= 1.04; 95% CI= 1.01-1.07; P= 2.5 × 10-3), and docosapentaenoic acids (ORDPA= 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.

AB - 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 [ORLA= 0.96; 95% confidence interval (CI)= 0.93-0.98; P= 5.2 × 10-4] and α-linolenic acid (ORALA= 0.95; 95% CI= 0.92-0.97; P= 5.4 × 10-5), whereas modest increased risks were observed for arachidonic (ORAA= 1.06; 95% CI= 1.03-1.08; P= 3.3 × 10-5), eicosapentaenoic (OREPA= 1.04; 95% CI= 1.01-1.07; P= 2.5 × 10-3), and docosapentaenoic acids (ORDPA= 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.

UR - http://www.scopus.com/inward/record.url?scp=85082780040&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85082780040&partnerID=8YFLogxK

U2 - 10.1158/1055-9965.EPI-19-0891

DO - 10.1158/1055-9965.EPI-19-0891

M3 - Article

C2 - 32051193

AN - SCOPUS:85082780040

SN - 1055-9965

VL - 29

SP - 860

EP - 870

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

IS - 4

ER -

Mendelian randomization of circulating polyunsaturated fatty acids and colorectal cancer risk

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