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

Authors

Philip C Haycock, Maria Carolina Borges, Kimberley Burrows, Rozenn N Lemaitre, Stephen Burgess, Nikhil K Khankari, Konstantinos K Tsilidis, Tom R Gaunt, Gibran Hemani, Jie Zheng, Therese Truong, Brenda M Birmann, Tracy OMara, Amanda B Spurdle, Mark M Iles, Matthew H Law, Susan L Slager, Fatemeh Saberi Hosnijeh, Daniela Mariosa, Michelle Cotterchio, James R Cerhan, Ulrike Peters, Stefan Enroth, Puya Gharahkhani, Loic Le Marchand, Ann C Williams, Robert C Block, Christopher I Amos, Rayjean J Hung, Wei Zheng, Marc J Gunter, George Davey Smith, Caroline Relton, Richard M Martin

Year of publication

2023

Journal

EBioMedicine

Volume

91

Issue

-

ISSN

2352-3964

Impact factor

11.205

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).