Journal article
The association between genetically elevated polyunsaturated fatty acids and risk of cancerResearch in context
EBioMedicine, Vol.91, 104510
05/01/2023
DOI: 10.1016/j.ebiom.2023.104510
PMCID: PMC10148095
PMID: 37086649
Abstract
Background: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. Methods: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. Findings: Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07–1.11]), esophageal squamous cell carcinoma (1.16 [1.06–1.26]), lung cancer (1.06 [1.03–1.08]) and basal cell carcinoma (1.05 [1.02–1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99–1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99–1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95–1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98–1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activity, mimicking a hypothetical intervention to reduce cancer risk, was associated (P < 0.0006) with increased risk of inflammatory bowel disease but not bleeding. Interpretation: The PUFA biosynthesis pathway may be an intervention target for prevention of colorectal cancer and esophageal squamous cell carcinoma but with potential for increased risk of inflammatory bowel disease. Funding: Cancer Resesrch UK (C52724/A20138, C18281/A19169). UK Medical Research Council (MR/P014054/1). National Institute for Health Research (NIHR202411). UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4). National Cancer Institute (R00 CA215360). National Institutes of Health (U01 CA164973, R01 CA60987, R01 CA72520, U01 CA74806, R01 CA55874, U01 CA164973 and U01 CA164973).
Details
- Title: Subtitle
- The association between genetically elevated polyunsaturated fatty acids and risk of cancerResearch in context
- Creators
- Philip C. HaycockMaria Carolina Borges - University of BristolKimberley Burrows - University of BristolRozenn N. Lemaitre - University of WashingtonStephen Burgess - University of CambridgeNikhil K. Khankari - Vanderbilt University Medical CenterKonstantinos K. TsilidisTom R. Gaunt - University of BristolGibran Hemani - University of BristolJie ZhengTherese Truong - InsermBrenda M. Birmann - Brigham and Women's HospitalTracy OMaraAmanda B. SpurdleMark M. IlesMatthew H. LawSusan L. Slager - Mayo ClinicFatemeh Saberi Hosnijeh - Utrecht UniversityDaniela Mariosa - Centre International de Recherche sur le CancerMichelle CotterchioJames R. Cerhan - Mayo ClinicUlrike PetersStefan Enroth - Uppsala UniversityPuya Gharahkhani - QIMR Berghofer Medical Research InstituteLoic Le Marchand - University of Hawaii SystemAnn C. Williams - University of BristolRobert C. Block - University of RochesterChristopher I. Amos - Baylor College of MedicineRayjean J. Hung - University of TorontoWei Zheng - Vanderbilt University Medical CenterMarc J. Gunter - Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, Lyon, FranceGeorge Davey Smith - University of BristolCaroline Relton - University of BristolRichard M. MartinNathan TintleTerri RiceIona ChengMark JenkinsSteve GallingerAlex J. CornishAmit SudJayaram VijayakrishnanMargaret WrenschMattias JohanssonAaron D. NormanAlison KleinAlyssa Clay-GilmourAndre FrankeAndres V. Ardisson KoratBill WheelerBjörn NilssonCaren SmithChew-Kiat HengCi SongDavid RiadiElizabeth B. ClausEva EllinghausEvgenia OstroumovaFlorent de VathaireGiovanni CugliariGiuseppe MatulloIrene Oi-Lin NgJeanette E. PassowJia Nee FooJiali HanJianjun LiuJill Barnholtz-SloanJoellen M. SchildkrautJohn MarisJoseph L. WiemelsKari HemminkiKeming YangLambertus A. KiemeneyLang WuLaufey AmundadottirMarc-Henri SternMarie-Christine BoutronMark P. PurdueMartin StanullaMelissa BondyMia GaudetLenha MobuchonNicola J. CampPak Chung ShamPascal GuénelPaul BrennanPhilip R. TaylorQuinn OstromRachael Stolzenberg-SolomonRajkumar DorajooRichard HoulstonRobert B. JenkinsSharon DiskinSonja I. BerndtSpiridon TsavachidisStephen J. ChannockTabitha HarrisonTessel GaleslootUlf GyllenstenVijai JosephY. ShiWenjian YangYi LinStephen K. Van Den EedenFatty Acids in Cancer Mendelian Randomization Collaboration
- Resource Type
- Journal article
- Publication Details
- EBioMedicine, Vol.91, 104510
- Publisher
- Elsevier
- DOI
- 10.1016/j.ebiom.2023.104510
- PMID
- 37086649
- PMCID
- PMC10148095
- ISSN
- 2352-3964
- eISSN
- 2352-3964
- Language
- English
- Date published
- 05/01/2023
- Academic Unit
- Epidemiology
- Record Identifier
- 9984399640102771
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