Pro-inflammatory fatty acid profile and colorectal cancer risk: A Mendelian randomisation analysis

Abstract

BackgroundWhile dietary fat has been established as a risk factor for colorectal cancer (CRC), associations between fatty acids (FAs) and CRC have been inconsistent. Using Mendelian randomisation (MR), we sought to evaluate associations between polyunsaturated (PUFA), monounsaturated (MUFA) and saturated FAs (SFAs) and CRC risk.MethodsWe analysed genotype data on 9254 CRC cases and 18,386 controls of European ancestry. Externally weighted polygenic risk scores were generated and used to evaluate associations with CRC per one standard deviation increase in genetically defined plasma FA levels.ResultsRisk reduction was observed for oleic and palmitoleic MUFAs (OROA = 0.77, 95% CI: 0.65–0.92, P = 3.9 × 10−3; ORPOA = 0.36, 95% CI: 0.15–0.84, P = 0.018). PUFAs linoleic and arachidonic acid had negative and positive associations with CRC respectively (ORLA = 0.95, 95% CI: 0.93–0.98, P = 3.7 × 10−4; ORAA = 1.05, 95% CI: 1.02–1.07, P = 1.7 × 10−4). The SFA stearic acid was associated with increased CRC risk (ORSA = 1.17, 95% CI: 1.01–1.35, P = 0.041).ConclusionResults from our analysis are broadly consistent with a pro-inflammatory FA profile having a detrimental effect in terms of CRC risk.

Mendelian Randomization Study for Genetically Predicted Polyunsaturated Fatty Acids Levels on Overall Cancer Risk and Mortality

“…Our results showed no association between PUFAs and overall cancer risk and mortality for a large change in genetically predicted PUFA levels (1 SD change correspond to a change of 16th percentile to the median in PUFA levels). Supported by approaches used in previous studies, we assumed a linear relationship between PUFAs and cancer risk, and disregard the need to consider potential nonlinear associations (31,37). Our MR inference cannot rule out predominantly null association(s) in our study, being a product of unmodeled nonlinear nonzero associations, which experienced a dilution or "cancelling out" effect; although this explanation is extremely unlikely.…”

“…We did not perform sex-stratified individual cancer risk analyses due to We performed fixed effect meta-analysis on colorectal cancer combining our estimates with those from May-Wilson and colleagues and the meta-analyzed result showed increased risk for AA and reduced risk for LA (AA, OR ¼ 1.05, 95% CI ¼ 1.03-1.07; LA, OR ¼ 0.95, 95% CI ¼ 0.93-0.97; ref. 37; Supplementary Table S4). Furthermore, we conducted a meta-analysis for prostate cancer risk of our UK Biobank estimates with a MR study by Khankari and colleagues (31).…”

“…We examined previously published results to assess if our selected SNP instruments had pleiotropic effects on selected potential confounders (height, BMI, and educational attainment; refs. 31,37,38). The result of the pleiotropy assessment can be found in Supplementary Tables S7-S9.…”

Genetic predisposition to mosaic Y chromosome loss in blood is associated with genomic instability in other tissues and susceptibility to non-haematological cancers

“…The renal cancer analysis used summary statistics from the Kidney Cancer GWAS Meta-Analysis Project of 10,784 cases of renal cell carcinoma and 20,406 controls 76 . Colorectal cancer summary statistics were from eight UK-based GWAS studies, totalling 22,372 colorectal cancer cases and 44,271 controls 77,78 . The summary statistics for overall lung cancer were from GWAS analyses of 29,266 lung cancer cases and 56,450 controls conducted by the International Lung Cancer Consortium 79 .…”

Dietary fatty acids and adipose tissue inflammation at the crossroad between obesity and colorectal cancer

“…The FA composition of AT reflects not only the dietary intake but also endogenous fat processing. Thus, changing the nature of the fat consumed has a profound influence on the type of FA available to the body and may alter AT composition [30] . In this regard, our most recent data show a higher arachidonic acid dietary intake in obese subjects as well as a higher arachidonic acid content of VAT [27,29] .…”