Role of circulating polyunsaturated fatty acids on cardiovascular diseases risk: analysis using Mendelian randomization and fatty acid genetic association data from over 114,000 UK Biobank participants

• Published in: BMC medicine 2022-06, Vol.20 (1), p.210-14, Article 210
• Main Authors: Borges, Maria Carolina, Haycock, Philip C, Zheng, Jie, Hemani, Gibran, Holmes, Michael V, Davey Smith, George, Hingorani, Aroon D, Lawlor, Deborah A
• Format: Article
• Language: English
• Subjects: Analysis; Aorta; Aortic aneurysms; Aortic valve; Biological Specimen Banks; Biomarkers; Cardiovascular disease; Cardiovascular diseases; Cardiovascular Diseases - epidemiology; Cardiovascular Diseases - genetics; Care and treatment; Cholesterol; Cholesterol, LDL; Congestive heart failure; Coronary artery; Coronary artery disease; Diagnosis; Docosahexaenoic acid; Fatty Acids; Fatty Acids, Unsaturated; Fibrillation; Genome-Wide Association Study; Genomes; Health aspects; Health risks; Heart diseases; Heart valves; Hemorrhage; Humans; Ischemia; Ischemic Stroke; Linoleic Acid; Low density lipoprotein; Low density lipoproteins; Measurement; Mendelian randomization; Mendelian Randomization Analysis; Metabolites; Omega-3 fatty acids; Pleiotropy; Polymorphism, Single Nucleotide - genetics; Polyunsaturated fatty acids; Randomization; Rheumatic heart disease; Risk analysis; Risk Factors; Single-nucleotide polymorphism; Statistical analysis; Stenosis; Stroke; Thromboembolism; United Kingdom - epidemiology; Unsaturated fatty acids; Vascular diseases
• ISSN: 1741-7015; 1741-7015
• DOI: 10.1186/s12916-022-02399-w

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. 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). 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. 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.