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. 2025 Jul 1;16(1):1226.
doi: 10.1007/s12672-025-03010-3.

Pan-cancer analysis of the impact of fatty acids: a two-sample and multivariable Mendelian randomization study

Xiaogen Kuang #  1   2   3 , Bingquan Wu #  1   2 , Dan Hu  4 , Juliet Matsika  1   2 , Chunliang Cheng  1   2 , Jiatong Xiao  1   2 , Zhiyong Cai  1   2 , Mingyong Li  3 , Jinbo Chen  1   2 , Weimin Zhou  5   6 , Bolong Liu  7
Affiliations

Pan-cancer analysis of the impact of fatty acids: a two-sample and multivariable Mendelian randomization study

Xiaogen Kuang et al. Discov Oncol. .

Abstract

Background: This study used Mendelian randomization (MR) to investigate the causal association between circulating fatty acids (FAs) and the incidence of 10 human cancer types.

Methods: Single nucleotide polymorphisms (SNPs) significantly associated with circulating FAs were selected from 500,000 UK Biobank blood samples and 114,999 plasma samples from a large GWAS. Summary-level data on 174,006 cancer patients were obtained from the FinnGen biobank. The inverse variance weighted method was used for causal estimation, with additional analyses including MR-Egger regression, weighted median, weighted mode, Cochrane Q test, MR-PRESSO global test, and leave-one-out analyses. Multivariable Mendelian randomization (MVMR) was applied to adjust for potential confounders.

Result: This study found a genetically causal effect of polyunsaturated FAs on kidney cancer incidence (OR: 1.528; 95% CI 1.164-2.266; P = 0.001), which remained significant after Bonferroni adjustment. The causal impact of omega-6, omega-3, and linoleic acid on kidney cancer risk was also observed (omega-6: OR = 1.586, P = 0.002; omega-3: OR = 1.311, P = 0.014; linoleic acid: OR = 1.527, P = 0.007). MVMR confirmed the consistent causal relationship (OR = 1.553, P = 0.0047) after adjusting for multiple variables. Results were validated in a larger cohort.

Conclusions: Higher circulating polyunsaturated FAs, especially omega-6, were associated with an increased risk of kidney cancer. Suggestive associations were found in small cell lung, rectal, bladder, pancreatic, and esophageal cancer.

Keywords: Kidney cancer; Mendelian randomization; Pan cancer analysis; Saturated fatty acid; Unsaturated fatty acid.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study only used publicly available data. No original data were collected. Ethical approval for each of the studies included in the investigation can be found in the original publications. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Overall study design of the MR analysis used to explore the relationship between fatty acids and the risk of cancer
Fig. 2
Fig. 2
Heatmap of the association between the incidence of 10 cancer types and three kinds of fatty acids using the IVW method. The circle sizes represent the p values of each association. The red circles indicate the significance after Bonferroni adjustment (1.66 × 10−3). The other four are suggestive associations
Fig. 3
Fig. 3
Causal association between four polyunsaturated FAs components and kidney, pancreatic, and cervical uterine cancer risk. One asterisk indicates suggestive evidence while two asterisks indicate statistical significance after a multiple comparison correction (P = 0.05/3 types of human cancer/4 fatty acids)
Fig. 4
Fig. 4
Causal association between circulating polyunsaturated and saturated FAs for kidney cancer risk by multivariable mendelian randomization after adjusting for BMI, HDL cholesterol, body size at age 10, diastolic blood pressure, and systolic blood pressure
Fig. 5
Fig. 5
Causal relationship between kidney cancer risk and circulating FAs validated in a more scaled cohort
See this image and copyright information in PMC

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