Dataset Information

Mendelian Randomization Analysis of n-6 Polyunsaturated Fatty Acid Levels and Pancreatic Cancer Risk.

ABSTRACT:

Background

Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome.

Methods

We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data.

Results

Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98-1.02; arachidonic acid OR = 1.00, 95% CI = 0.99-1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87-1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex.

Conclusions

Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk.

Impact

These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.

SUBMITTER: Ghoneim DH

PROVIDER: S-EPMC7710600 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

Mendelian Randomization Analysis of n-6 Polyunsaturated Fatty Acid Levels and Pancreatic Cancer Risk.

Ghoneim Dalia H DH Zhu Jingjing J Zheng Wei W Long Jirong J Murff Harvey J HJ Ye Fei F Setiawan Veronica Wendy VW Wilkens Lynne R LR Khankari Nikhil K NK Haycock Philip P Antwi Samuel O SO Yang Yaohua Y Arslan Alan A AA Beane Freeman Laura E LE Bracci Paige M PM Canzian Federico F Du Mengmeng M Gallinger Steven S Giles Graham G GG Goodman Phyllis J PJ Kooperberg Charles C Le Marchand Loïc L Neale Rachel E RE Scelo Ghislaine G Visvanathan Kala K White Emily E Albanes Demetrius D Amiano Pilar P Andreotti Gabriella G Babic Ana A Bamlet William R WR Berndt Sonja I SI Brais Lauren K LK Brennan Paul P Bueno-de-Mesquita Bas B Buring Julie E JE Campbell Peter T PT Rabe Kari G KG Chanock Stephen J SJ Duggal Priya P Fuchs Charles S CS Gaziano J Michael JM Goggins Michael G MG Hackert Thilo T Hassan Manal M MM Helzlsouer Kathy J KJ Holly Elizabeth A EA Hoover Robert N RN Katske Verena V Kurtz Robert C RC Lee I-Min IM Malats Núria N Milne Roger L RL Murphy Neil N Oberg Ann L AL Porta Miquel M Rothman Nathaniel N Sesso Howard D HD Silverman Debra T DT Thompson Ian M IM Wactawski-Wende Jean J Wang Xiaoliang X Wentzensen Nicolas N Yu Herbert H Zeleniuch-Jacquotte Anne A Yu Kai K Wolpin Brian M BM Jacobs Eric J EJ Duell Eric J EJ Risch Harvey A HA Petersen Gloria M GM Amundadottir Laufey T LT Kraft Peter P Klein Alison P AP Stolzenberg-Solomon Rachel Z RZ Shu Xiao-Ou XO Wu Lang L

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20200923 12

<h4>Background</h4>Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome.<h4>Methods</h4>We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 co ...[more]

PMID: 32967863

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Project description:BackgroundResults from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk.MethodsInformation was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined.ResultsModest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [ORLA = 0.96; 95% confidence interval (CI) = 0.93-0.98; P = 5.2 × 10-4] and α-linolenic acid (ORALA = 0.95; 95% CI = 0.92-0.97; P = 5.4 × 10-5), whereas modest increased risks were observed for arachidonic (ORAA = 1.06; 95% CI = 1.03-1.08; P = 3.3 × 10-5), eicosapentaenoic (OREPA = 1.04; 95% CI = 1.01-1.07; P = 2.5 × 10-3), and docosapentaenoic acids (ORDPA = 1.03; 95% CI = 1.01-1.06; P = 1.2 × 10-2). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses.ConclusionsOur study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk.ImpactThe interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.

Project description:IntroductionDespite numerous observational studies reporting a positive correlation between polyunsaturated fatty acids (PUFAs) and the risk of sepsis and mortality, the causation of such an association has yet to be firmly established. Thus, our study aimed to undertake the Mendelian randomization (MR) approach to scrutinize the potential causalities of PUFAs with sepsis and mortality risk.MethodsWe conducted the MR investigation using genome-wide association study (GWAS) summary statistics of PUFAs [including omega-3 fatty acids (omega-3), omega-6 fatty acids (omega-6), the ratio of omega-6 to omega-3 fatty acids (omega-6:3), docosahexaenoic acid (DHA), linoleic acid (LA)], sepsis, and sepsis mortality. We utilized the GWAS summary data from the UK Biobank. To establish reliable causality, we employed the inverse-variance weighted (IVW) method as the primary analytical approach, together with four additional MR methods. In addition, we performed heterogeneity and horizontal pleiotropy assessments using Cochrane's Q test and MR-Egger intercept test, respectively. Finally, we performed a series of sensitivity analyses to enhance the precision and veracity of our findings.ResultsThe IVW method showed that genetically predicted omega-3 [odd ratio (OR) 0.914, 95% confidence interval (CI) 0.845-0.987, P = 0.023] and DHA (OR 0.893, 95% CI 0.815-0.979, P = 0.015) were suggestively linked to a decreased risk of sepsis. Furthermore, genetically predicted DHA (OR 0.819, 95% CI 0.681-0.986, P = 0.035) was suggestively associated with a reduced risk of sepsis-related death. Conversely, the omega-6:3 ratio (OR 1.177, 95% CI 1.011-1.371, P = 0.036) was suggestively linked to an increased risk of sepsis-induced mortality. On the basis of the MR-Egger intercept assessment, it appears that our MR examination was not influenced by any horizontal pleiotropy (all P > 0.05). Moreover, the reliability of the estimated causal association was confirmed by the sensitivity analyses.ConclusionOur study supported the casual effect between PUFAs and susceptibility to sepsis and sepsis-related death. Our findings underline the importance of specific PUFAs levels, particularly for individuals with a genetic susceptibility to sepsis. Further research is needed to confirm these findings and investigate the underlying mechanisms.

Project description:IntroductionObservational studies demonstrated controversial effect of polyunsaturated fatty acids (PUFAs) on Parkinson's disease (PD) with limited causality evidence. Randomized control trials showed possible improvement in PD symptoms with PUFA supplement but had small study population and limited intervention time.MethodsA two-sample Mendelian randomization was designed to evaluate the causal relevance between PUFAs and PD, using genetic variants of PUFAs as instrumental variables and PD data from the largest genome-wide association study as outcome. Inverse variance weighted (IVW) method was applied to obtain the primary outcome. Mendelian randomization Egger regression, weighted median and weighted mode methods were exploited to assist result analyses. Strict Mendelian randomization and multivariable Mendelian randomization (MVMR) were used to estimate direct effects of PUFAs on PD, eliminating pleiotropic effect. Debiased inverse variance weighted estimator was implemented when weak instrument bias was introduced into the analysis. A variety of sensitivity analyses were utilized to assess validity of the results.ResultsOur study included 33,674 PD cases and 449,056 controls. Higher plasma level of arachidonic acid (AA) was associated with a 3% increase of PD risk per 1-standard deviation (SD) increase of AA (IVW; Odds ratio (OR)=1.03 [95% confidence interval (CI) 1.01-1.04], P = 2.24E-04). After MVMR (IVW; OR=1.03 [95% CI 1.02-1.04], P =6.15E-08) and deletion of pleiotropic single-nucleotide polymorphisms overlapping with other lipids (IVW; OR=1.03 [95% CI 1.01-1.05], P =5.88E-04), result was still significant. Increased level of eicosapentaenoic acid (EPA) showed possible relevance with increased PD risk after adjustment of pleiotropy (MVMR; OR=1.05 [95% CI 1.01-1.08], P =5.40E-03). Linoleic acid (LA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and alpha-linolenic acid (ALA) were found not causally relevant to PD risk. Various sensitivity analyses verified the validity of our results. In conclusion, our findings from Mendelian randomization suggested that elevated levels of AA and possibly EPA might be linked to a higher risk of PD. No association between PD risk and LA, DHA, DPA, or ALA was found.DiscussionThe odds ratio for plasma AA and PD risk was weak. It is important to approach our results with caution in clinical practice and to conduct additional studies on the relationship between PUFAs and PD risk.

Dataset Information

Mendelian Randomization Analysis of n-6 Polyunsaturated Fatty Acid Levels and Pancreatic Cancer Risk.

Background

Methods

Results

Conclusions

Impact

Publications

Mendelian Randomization Analysis of n-6 Polyunsaturated Fatty Acid Levels and Pancreatic Cancer Risk.

Similar Datasets

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