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

Laboratory Medicine and Pathology

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

7 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

ASJC Scopus subject areas

General Medicine

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10.1158/1055-9965.EPI-19-0891

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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{9ab084ea381d4e60bfc92e18538fea1c,

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 = "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

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.

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

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

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AN - SCOPUS:85082780040

SN - 1055-9965

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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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