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Article: The association between genetically elevated polyunsaturated fatty acids and risk of cancer

TitleThe association between genetically elevated polyunsaturated fatty acids and risk of cancer
Authors
KeywordsCancer risk
Delta-5 desaturase
Delta-6 desaturase
Mendelian randomization
Omega 3
Omega 6
Polyunsaturated fatty acids
Issue Date11-Jan-2023
PublisherElsevier
Citation
EBioMedicine, 2023, v. 91 How to Cite?
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% con-fidence 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.


Persistent Identifierhttp://hdl.handle.net/10722/331733
ISSN
2023 Impact Factor: 9.7
2023 SCImago Journal Rankings: 3.193
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHaycock, PC-
dc.contributor.authorBorges, MC-
dc.contributor.authorBurrows, K-
dc.contributor.authorLemaitre, RN-
dc.contributor.authorBurgess, S-
dc.contributor.authorKhankari, NK-
dc.contributor.authorTsilidis, KK-
dc.contributor.authorGaunt, TR-
dc.contributor.authorHemani, G-
dc.contributor.authorZheng, J-
dc.contributor.authorTruong, T-
dc.contributor.authorBirmann, BM-
dc.contributor.authorOMara, T-
dc.contributor.authorSpurdle, AB-
dc.contributor.authorIles, MM-
dc.contributor.authorLaw, MH-
dc.contributor.authorSlager, SL-
dc.contributor.authorHosnijeh, FS-
dc.contributor.authorMariosa, D-
dc.contributor.authorCotterchio, M-
dc.contributor.authorCerhan, JR-
dc.contributor.authorPeters, U-
dc.contributor.authorEnroth, S-
dc.contributor.authorGharahkhani, P-
dc.contributor.authorLe Marchand, L-
dc.contributor.authorWilliams, AC-
dc.contributor.authorBlock, RC-
dc.contributor.authorAmos, CI-
dc.contributor.authorHung, RJ-
dc.contributor.authorZheng, W-
dc.contributor.authorGunter, MJ-
dc.contributor.authorSmith, GD-
dc.contributor.authorRelton, C-
dc.contributor.authorMartin, RM-
dc.contributor.authorFatty Acids in Cancer Mendelian Randomization Collaboration-
dc.contributor.authorNg, Irene Oi Lin-
dc.date.accessioned2023-09-21T06:58:26Z-
dc.date.available2023-09-21T06:58:26Z-
dc.date.issued2023-01-11-
dc.identifier.citationEBioMedicine, 2023, v. 91-
dc.identifier.issn2352-3964-
dc.identifier.urihttp://hdl.handle.net/10722/331733-
dc.description.abstract<p>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% con-fidence 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.<br></p>-
dc.languageeng-
dc.publisherElsevier-
dc.relation.ispartofEBioMedicine-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectCancer risk-
dc.subjectDelta-5 desaturase-
dc.subjectDelta-6 desaturase-
dc.subjectMendelian randomization-
dc.subjectOmega 3-
dc.subjectOmega 6-
dc.subjectPolyunsaturated fatty acids-
dc.titleThe association between genetically elevated polyunsaturated fatty acids and risk of cancer-
dc.typeArticle-
dc.identifier.doi10.1016/j.ebiom.2023.104510-
dc.identifier.scopuseid_2-s2.0-85152746090-
dc.identifier.volume91-
dc.identifier.eissn2352-3964-
dc.identifier.isiWOS:000992570900001-
dc.identifier.issnl2352-3964-

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