Mendelian randomization of circulating polyunsaturated fatty acids and colorectal cancer risk.
Khankari NK, Banbury BL, Borges MC, Haycock P, Albanes D, Arndt V, Berndt SI, Bézieau S, Brenner H, 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
BACKGROUND: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFAs) and colorectal cancer (CRC) 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 CRC risk.
METHODS: Information was leveraged from GWAS regarding PUFA-associated single nucleotide polymorphisms (SNPs) to create weighted genetic scores (wGSs) representing genetically-predicted circulating blood PUFAs for 11,016 non-Hispanic white CRC cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per standard deviation increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on CRC risk were also examined.
RESULTS: Modest CRC risk reductions were observed per standard deviation increase in circulating linoleic acid (ORLA=0.96; 95% CI=0.93-0.98; p=5.2x10-4), α-linolenic acid (ORALA=0.95; 95% CI=0.92-0.97; p=5.4x10-5); whereas modest increased risks were observed for arachidonic acid (ORAA=1.06; 95% CI=1.03-1.08; p=3.3x10-5), eicosapentaenoic (OREPA=1.04; 95% CI=1.01-1.07; p=2.5x10-3), and docosapentaenoic acids (ORDPA=1.03; 95% CI=1.01-1.06; p=1.2x10-2. Each of these effects were stronger among aspirin/NSAID non-users in the stratified analyses.
CONCLUSIONS: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced CRC risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased CRC risk.
IMPACT: The interaction of PUFAs with aspirin/NSAID use indicates a shared CRC inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on CRC.
- 2014-0244: Colorectal Tumor Risk Prediction in the PLCO Trial (ULRIKE PETERS - 2014)