| Title: | The association between genetically elevated polyunsaturated fatty acids and risk of cancer |
| Journal: | EBioMedicine |
| Published: | 20 Apr 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37086649/ |
| DOI: | https://doi.org/10.1016/j.ebiom.2023.104510 |
| URL: | http://www.thelancet.com/article/S2352396423000750/pdf |
Publication 11363
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Abstract
BACKGROUND: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain.</p>
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.</p>
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.</p>
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.</p>
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).</p>
117 Authors
- Fatty Acids in Cancer Mendelian Randomization Collaboration
- Nathan Tintle
- Terri Rice
- Iona Cheng
- Mark Jenkins
- Steve Gallinger
- Alex J. Cornish
- Amit Sud
- Jayaram Vijayakrishnan
- Margaret Wrensch
- Mattias Johansson
- Aaron D. Norman
- Alison Klein
- Alyssa Clay-Gilmour
- Andre Franke
- Andres V. Ardisson Korat
- Bill Wheeler
- Björn Nilsson
- Caren Smith
- Chew-Kiat Heng
- Ci Song
- David Riadi
- Elizabeth B. Claus
- Eva Ellinghaus
- Evgenia Ostroumova
- Hosnijeh
- Florent de Vathaire
- Giovanni Cugliari
- Giuseppe Matullo
- Irene Oi-Lin Ng
- Jeanette E. Passow
- Jia Nee Foo
- Jiali Han
- Jianjun Liu
- Jill Barnholtz-Sloan
- Joellen M. Schildkraut
- John Maris
- Joseph L. Wiemels
- Kari Hemminki
- Keming Yang
- Lambertus A. Kiemeney
- Lang Wu
- Laufey Amundadottir
- Marc-Henri Stern
- Marie-Christine Boutron
- Mark Martin Iles
- Mark P. Purdue
- Martin Stanulla
- Melissa Bondy
- Mia Gaudet
- Lenha Mobuchon
- Nicola J. Camp
- Pak Chung Sham
- Pascal Guénel
- Paul Brennan
- Philip R. Taylor
- Quinn Ostrom
- Rachael Stolzenberg-Solomon
- Rajkumar Dorajoo
- Richard Houlston
- Robert B. Jenkins
- Sharon Diskin
- Sonja I. Berndt
- Spiridon Tsavachidis
- Stephen J. Channock
- Tabitha Harrison
- Tessel Galesloot
- Ulf Gyllensten
- Vijai Joseph
- Y. Shi
- Wenjian Yang
- Yi Lin
- Stephen K. Van Den Eeden
- 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
- ACCC
- CCFR-CORECT-GECCO
- EPITHYR
- InterLymph
- MMAC
- ECAC
- ILCCO
- The PRACTICAL Consortium
- PanScan
- PanC4
- Christopher I. Amos
- Rayjean J. Hung
- Wei Zheng
- Marc J. Gunter
- George Davey Smith
- Caroline Relton
- Richard M. Martin
1 Application
| Application ID | Title |
|---|---|
| 15825 | MR-Base: an online resource for Mendelian randomization using summary data |
Enabling scientific discoveries that improve human health