Maria Carolina Borges1,2, Philip C Haycock3,4, Jie Zheng3,4, Gibran Hemani3,4, Michael V Holmes5, George Davey Smith3,4, Aroon D Hingorani6,7,8,9, Deborah A Lawlor3,4,10. 1. MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK. m.c.borges@bristol.ac.uk. 2. Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. m.c.borges@bristol.ac.uk. 3. MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK. 4. Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. 5. MRC Population Health Research Unit (MRC PHRU), Nuffield Department of Population Health, University of Oxford, Oxford, UK. 6. Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK. 7. UCL BHF Research Accelerator, London, UK. 8. Health Data Research UK, Institute of Health Informatics, University College London, London, UK. 9. UCL NIHR Biomedical Research Centre, London, UK. 10. NIHR Bristol Biomedical Research Centre, Bristol, UK.
Abstract
BACKGROUND: Despite early interest in the health effects of polyunsaturated fatty acids (PUFA), there is still substantial controversy and uncertainty on the evidence linking PUFA to cardiovascular diseases (CVDs). We investigated the effect of plasma concentration of omega-3 PUFA (i.e. docosahexaenoic acid (DHA) and total omega-3 PUFA) and omega-6 PUFA (i.e. linoleic acid and total omega-6 PUFA) on the risk of CVDs using Mendelian randomization. METHODS: We conducted the largest genome-wide association study (GWAS) of circulating PUFA to date including a sample of 114,999 individuals and incorporated these data in a two-sample Mendelian randomization framework to investigate the involvement of circulating PUFA on a wide range of CVDs in up to 1,153,768 individuals of European ancestry (i.e. coronary artery disease, ischemic stroke, haemorrhagic stroke, heart failure, atrial fibrillation, peripheral arterial disease, aortic aneurysm, venous thromboembolism and aortic valve stenosis). RESULTS: GWAS identified between 46 and 64 SNPs for the four PUFA traits, explaining 4.8-7.9% of circulating PUFA variance and with mean F statistics >100. Higher genetically predicted DHA (and total omega-3 fatty acids) concentration was related to higher risk of some cardiovascular endpoints; however, these findings did not pass our criteria for multiple testing correction and were attenuated when accounting for LDL-cholesterol through multivariable Mendelian randomization or excluding SNPs in the vicinity of the FADS locus. Estimates for the relation between higher genetically predicted linoleic acid (and total omega-6) concentration were inconsistent across different cardiovascular endpoints and Mendelian randomization methods. There was weak evidence of higher genetically predicted linoleic acid being related to lower risk of ischemic stroke and peripheral artery disease when accounting by LDL-cholesterol. CONCLUSIONS: We have conducted the largest GWAS of circulating PUFA to date and the most comprehensive Mendelian randomization analyses. Overall, our Mendelian randomization findings do not support a protective role of circulating PUFA concentration on the risk of CVDs. However, horizontal pleiotropy via lipoprotein-related traits could be a key source of bias in our analyses.
BACKGROUND: Despite early interest in the health effects of polyunsaturated fatty acids (PUFA), there is still substantial controversy and uncertainty on the evidence linking PUFA to cardiovascular diseases (CVDs). We investigated the effect of plasma concentration of omega-3 PUFA (i.e. docosahexaenoic acid (DHA) and total omega-3 PUFA) and omega-6 PUFA (i.e. linoleic acid and total omega-6 PUFA) on the risk of CVDs using Mendelian randomization. METHODS: We conducted the largest genome-wide association study (GWAS) of circulating PUFA to date including a sample of 114,999 individuals and incorporated these data in a two-sample Mendelian randomization framework to investigate the involvement of circulating PUFA on a wide range of CVDs in up to 1,153,768 individuals of European ancestry (i.e. coronary artery disease, ischemic stroke, haemorrhagic stroke, heart failure, atrial fibrillation, peripheral arterial disease, aortic aneurysm, venous thromboembolism and aortic valve stenosis). RESULTS: GWAS identified between 46 and 64 SNPs for the four PUFA traits, explaining 4.8-7.9% of circulating PUFA variance and with mean F statistics >100. Higher genetically predicted DHA (and total omega-3 fatty acids) concentration was related to higher risk of some cardiovascular endpoints; however, these findings did not pass our criteria for multiple testing correction and were attenuated when accounting for LDL-cholesterol through multivariable Mendelian randomization or excluding SNPs in the vicinity of the FADS locus. Estimates for the relation between higher genetically predicted linoleic acid (and total omega-6) concentration were inconsistent across different cardiovascular endpoints and Mendelian randomization methods. There was weak evidence of higher genetically predicted linoleic acid being related to lower risk of ischemic stroke and peripheral artery disease when accounting by LDL-cholesterol. CONCLUSIONS: We have conducted the largest GWAS of circulating PUFA to date and the most comprehensive Mendelian randomization analyses. Overall, our Mendelian randomization findings do not support a protective role of circulating PUFA concentration on the risk of CVDs. However, horizontal pleiotropy via lipoprotein-related traits could be a key source of bias in our analyses.
Authors: Jack Bowden; Fabiola Del Greco M; Cosetta Minelli; George Davey Smith; Nuala Sheehan; John Thompson Journal: Stat Med Date: 2017-01-23 Impact factor: 2.373
Authors: Sonia Shah; Albert Henry; Carolina Roselli; Honghuang Lin; Garðar Sveinbjörnsson; Ghazaleh Fatemifar; Åsa K Hedman; Jemma B Wilk; Michael P Morley; Mark D Chaffin; Anna Helgadottir; Niek Verweij; Abbas Dehghan; Peter Almgren; Charlotte Andersson; Krishna G Aragam; Johan Ärnlöv; Joshua D Backman; Mary L Biggs; Heather L Bloom; Jeffrey Brandimarto; Michael R Brown; Leonard Buckbinder; David J Carey; Daniel I Chasman; Xing Chen; Xu Chen; Jonathan Chung; William Chutkow; James P Cook; Graciela E Delgado; Spiros Denaxas; Alexander S Doney; Marcus Dörr; Samuel C Dudley; Michael E Dunn; Gunnar Engström; Tõnu Esko; Stephan B Felix; Chris Finan; Ian Ford; Mohsen Ghanbari; Sahar Ghasemi; Vilmantas Giedraitis; Franco Giulianini; John S Gottdiener; Stefan Gross; Daníel F Guðbjartsson; Rebecca Gutmann; Christopher M Haggerty; Pim van der Harst; Craig L Hyde; Erik Ingelsson; J Wouter Jukema; Maryam Kavousi; Kay-Tee Khaw; Marcus E Kleber; Lars Køber; Andrea Koekemoer; Claudia Langenberg; Lars Lind; Cecilia M Lindgren; Barry London; Luca A Lotta; Ruth C Lovering; Jian'an Luan; Patrik Magnusson; Anubha Mahajan; Kenneth B Margulies; Winfried März; Olle Melander; Ify R Mordi; Thomas Morgan; Andrew D Morris; Andrew P Morris; Alanna C Morrison; Michael W Nagle; Christopher P Nelson; Alexander Niessner; Teemu Niiranen; Michelle L O'Donoghue; Anjali T Owens; Colin N A Palmer; Helen M Parry; Markus Perola; Eliana Portilla-Fernandez; Bruce M Psaty; Kenneth M Rice; Paul M Ridker; Simon P R Romaine; Jerome I Rotter; Perttu Salo; Veikko Salomaa; Jessica van Setten; Alaa A Shalaby; Diane T Smelser; Nicholas L Smith; Steen Stender; David J Stott; Per Svensson; Mari-Liis Tammesoo; Kent D Taylor; Maris Teder-Laving; Alexander Teumer; Guðmundur Thorgeirsson; Unnur Thorsteinsdottir; Christian Torp-Pedersen; Stella Trompet; Benoit Tyl; Andre G Uitterlinden; Abirami Veluchamy; Uwe Völker; Adriaan A Voors; Xiaosong Wang; Nicholas J Wareham; Dawn Waterworth; Peter E Weeke; Raul Weiss; Kerri L Wiggins; Heming Xing; Laura M Yerges-Armstrong; Bing Yu; Faiez Zannad; Jing Hua Zhao; Harry Hemingway; Nilesh J Samani; John J V McMurray; Jian Yang; Peter M Visscher; Christopher Newton-Cheh; Anders Malarstig; Hilma Holm; Steven A Lubitz; Naveed Sattar; Michael V Holmes; Thomas P Cappola; Folkert W Asselbergs; Aroon D Hingorani; Karoline Kuchenbaecker; Patrick T Ellinor; Chim C Lang; Kari Stefansson; J Gustav Smith; Ramachandran S Vasan; Daniel I Swerdlow; R Thomas Lumbers Journal: Nat Commun Date: 2020-01-09 Impact factor: 14.919
Authors: Brian A Ference; Jennifer G Robinson; Robert D Brook; Alberico L Catapano; M John Chapman; David R Neff; Szilard Voros; Robert P Giugliano; George Davey Smith; Sergio Fazio; Marc S Sabatine Journal: N Engl J Med Date: 2016-12-01 Impact factor: 91.245
Authors: Lee Hooper; Lena Al-Khudairy; Asmaa S Abdelhamid; Karen Rees; Julii S Brainard; Tracey J Brown; Sarah M Ajabnoor; Alex T O'Brien; Lauren E Winstanley; Daisy H Donaldson; Fujian Song; Katherine Ho Deane Journal: Cochrane Database Syst Rev Date: 2018-11-29
Authors: Asmaa S Abdelhamid; Nicole Martin; Charlene Bridges; Julii S Brainard; Xia Wang; Tracey J Brown; Sarah Hanson; Oluseyi F Jimoh; Sarah M Ajabnoor; Katherine Ho Deane; Fujian Song; Lee Hooper Journal: Cochrane Database Syst Rev Date: 2018-11-27
Authors: So-Youn Shin; Eric B Fauman; Ann-Kristin Petersen; Jan Krumsiek; Rita Santos; Jie Huang; Matthias Arnold; Idil Erte; Vincenzo Forgetta; Tsun-Po Yang; Klaudia Walter; Cristina Menni; Lu Chen; Louella Vasquez; Ana M Valdes; Craig L Hyde; Vicky Wang; Daniel Ziemek; Phoebe Roberts; Li Xi; Elin Grundberg; Melanie Waldenberger; J Brent Richards; Robert P Mohney; Michael V Milburn; Sally L John; Jeff Trimmer; Fabian J Theis; John P Overington; Karsten Suhre; M Julia Brosnan; Christian Gieger; Gabi Kastenmüller; Tim D Spector; Nicole Soranzo Journal: Nat Genet Date: 2014-05-11 Impact factor: 38.330
Authors: Jack Bowden; Fabiola Del Greco M; Cosetta Minelli; George Davey Smith; Nuala A Sheehan; John R Thompson Journal: Int J Epidemiol Date: 2016-12-01 Impact factor: 7.196
Authors: Susanne Jäger; Rafael Cuadrat; Per Hoffmann; Clemens Wittenbecher; Matthias B Schulze Journal: Nutrients Date: 2020-07-28 Impact factor: 5.717