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 journalArticle

3 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 (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.

Original languageEnglish (US)
Pages (from-to)860-870
Number of pages11
JournalCancer Epidemiology Biomarkers and Prevention
Volume29
Issue number4
DOIs
StatePublished - 2020

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

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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