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

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]; P_{heterogeneity} = 0.25), urinary system cancers (1.03 [0.99-1.06], P_{heterogeneity} = 0.51), nervous system cancers (0.99 [0.95-1.03], P_{heterogeneity} = 0.92) or blood cancers (1.01 [0.98-1.04], P_{heterogeneity} = 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).

Keywords: Cancer risk; Delta-5 desaturase; Delta-6 desaturase; Mendelian randomization; Omega 3; Omega 6; Polyunsaturated fatty acids.

Fig. 1

Association between genetically proxied polyunsaturated fatty acid desaturase activity and risk of cancer. Plotted data indicate odds ratios for cancer per standard deviation increase in polyunsaturated fatty acid desaturase activity instrumented by rs174546. Point sizes are proportional to the inverse of the variance for the log odds ratio. An alpha threshold of 0.0007 (0.05/67 cancers) was used to identify associations. Abbreviations: OR, odds ratio; SD, standard deviation; CI, confidence interval; nmsc, non-melanoma skin cancer, ER, estrogen receptor; LMP, low malignant potential; LG, low grade; SCC, squamous cell carcinoma; PUFA, polyunsaturated fatty acid.

Fig. 2

Association between genetically elevated polyunsaturated fatty acids and risk of colorectal cancer in 58,131 cases and 67,347 controls. Outcome summary data for colorectal cancer were derived from a meta-analysis of the GECCO, CORECT and CCFR studies. Summary data for fatty acid exposures were derived from either the CHARGE consortium or UK Biobank. The Q P value was derived from a Cochran's Q test for heterogeneity in MR results amongst SNPs in the genetic instrument. The P value column represents the P value for association between the PUFA and cancer, derived from inverse-variance weighted linear regression (>1 SNP) or a Wald ratio test (1 SNP). The “No. SNPs” column represents the number of SNPs present in the genetic instrument. The FADS region (proxied by rs174546) was either included (black data points) or excluded (red data points) from the genetic instrument. Individual PUFAs within the omega 3 and omega 6 sections are sorted according to chain length (shorter to longer). Abbreviations: PUFAs, polyunsaturated fatty acids; SD, standard deviation.

Fig. 3

Association between genetically elevated polyunsaturated fatty acids and risk of lung cancer in 31,937 cases and 428,466 controls. Outcome summary data for lung cancer were derived from a meta-analysis of the ILCCO and UK Biobank. Summary data for fatty acid exposures were derived from either the CHARGE consortium or UK Biobank. The Q P value was derived from a Cochran's Q test for heterogeneity in MR results amongst SNPs in the genetic instrument. The P value column represents the P value for association between the PUFA and cancer, derived from inverse-variance weighted linear regression (>1 SNP) or a Wald ratio test (1 SNP). The “No. SNPs” column represents the number of SNPs present in the genetic instrument. The FADS region (proxied by rs174546) was either included (black data points) or excluded (red data points) from the genetic instrument. Individual PUFAs within the omega 3 and omega 6 sections are sorted according to chain length (shorter to longer). Abbreviations: PUFAs, polyunsaturated fatty acids; SD, standard deviation.