{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T19:54:06Z","timestamp":1780084446108,"version":"3.54.0"},"reference-count":58,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T00:00:00Z","timestamp":1619568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Arachidonic acid (AA), a major long-chain omega-6 polyunsaturated fatty acid, is associated with ischemic heart disease (IHD) and stroke. We assessed bi-directional associations of AA synthesis reflected by plasma phospholipid AA with CVD risk factors, and identified mediators of associations of AA with IHD and stroke using Mendelian randomization (MR). We used two-sample MR to assess bi-directional associations of AA synthesis with lipids, blood pressure, adiposity, and markers of inflammation and coagulation. We used multivariable MR to assess mediators of associations of AA with IHD and stroke. Genetically predicted AA (% of total fatty acids increase) was positively associated with apolipoprotein B (ApoB, 0.022 standard deviations (SD), 95% confidence interval (CI) 0.010, 0.034), high-density (0.030 SD, 95% CI 0.012, 0.049) and low-density lipoprotein cholesterol (LDL-C, 0.016 SD, 95% CI 0.004, 0.027) and lower triglycerides (\u22120.031 SD, 95% CI \u22120.049, \u22120.012) but not with other traits. Genetically predicted these traits gave no association with AA. The association of AA with IHD was attenuated adjusting for ApoB or LDL-C. Genetically predicted AA was associated with lipids but not other traits. Given ApoB is thought to be the key lipid in IHD, the association of AA with IHD is likely mediated by ApoB.<\/jats:p>","DOI":"10.3390\/nu13051489","type":"journal-article","created":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T22:29:07Z","timestamp":1619648947000},"page":"1489","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Associations of Arachidonic Acid Synthesis with Cardiovascular Risk Factors and Relation to Ischemic Heart Disease and Stroke: A Univariable and Multivariable Mendelian Randomization Study"],"prefix":"10.3390","volume":"13","author":[{"given":"Ting","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6136-1836","authenticated-orcid":false,"given":"Shiu-Lun","family":"Au Yeung","sequence":"additional","affiliation":[{"name":"School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Mary","family":"Schooling","sequence":"additional","affiliation":[{"name":"School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"},{"name":"School of Public Health and Health Policy, City University of New York, New York, NY 10027, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1001\/jama.1957.62980170024007e","article-title":"Diet and the epidemiology of coronary heart disease","volume":"164","author":"Keys","year":"1957","journal-title":"J. Am. Med. Assoc."},{"key":"ref_2","unstructured":"US Senate Select Committee on Nutrition and Human Needs (1977). Dietary Goals for the United States."},{"key":"ref_3","unstructured":"(2021, January 10). US Department of Health and Human Services and U.S. 2015\u20132020 Dietary Guidelines for Americans, Available online: https:\/\/health.gov\/dietaryguidelines\/2015\/guidelines\/."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1056\/NEJMoa1812792","article-title":"Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia","volume":"380","author":"Bhatt","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1001\/jamacardio.2017.5205","article-title":"Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77917 Individuals","volume":"3","author":"Aung","year":"2018","journal-title":"JAMA Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1186\/s12944-019-1039-y","article-title":"Intake of arachidonic acid-containing lipids in adult humans: Dietary surveys and clinical trials","volume":"18","author":"Kawashima","year":"2019","journal-title":"Lipids Health Dis."},{"key":"ref_7","first-page":"100216","article-title":"Eicosanoids: Atherosclerosis and cardiometabolic health","volume":"19","author":"Piper","year":"2020","journal-title":"J. Clin. Transl. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"103189","DOI":"10.1016\/j.ebiom.2020.103189","article-title":"The associations of plasma phospholipid arachidonic acid with cardiovascular diseases: A Mendelian randomization study","volume":"63","author":"Zhang","year":"2021","journal-title":"EBioMedicine"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Yuan, S., Back, M., Bruzelius, M., Mason, A.M., Burgess, S., and Larsson, S. (2019). Plasma Phospholipid Fatty Acids, FADS1 and Risk of 15 Cardiovascular Diseases: A Mendelian Randomisation Study. Nutrients, 11.","DOI":"10.3390\/nu11123001"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/s12937-020-00582-4","article-title":"Roles for circulating polyunsaturated fatty acids in ischemic stroke and modifiable factors: A Mendelian randomization study","volume":"19","author":"Yuan","year":"2020","journal-title":"Nutr. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3945\/ajcn.2008.26761","article-title":"Association of serum n-6 and n-3 polyunsaturated fatty acids with lipids in 3 populations of middle-aged men","volume":"90","author":"Motoyama","year":"2009","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1210\/jc.2005-1303","article-title":"Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers","volume":"91","author":"Ferrucci","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.plefa.2017.12.003","article-title":"Arachidonic acid supplementation modulates blood and skeletal muscle lipid profile with no effect on basal inflammation in resistance exercise trained men","volume":"128","author":"Markworth","year":"2018","journal-title":"Prostaglandinsleukotrienesand Essent. Fat. Acids"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1017\/S0007114507734566","article-title":"Effects of arachidonate-enriched triacylglycerol supplementation on serum fatty acids and platelet aggregation in healthy male subjects with a fish diet","volume":"98","author":"Kusumoto","year":"2007","journal-title":"Br. J. Nutr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1007\/s11745-997-0056-6","article-title":"The effect of dietary arachidonic acid on plasma lipoprotein distributions, apoproteins, blood lipid levels, and tissue fatty acid composition in humans","volume":"32","author":"Nelson","year":"1997","journal-title":"Lipids"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1186\/1476-511X-10-241","article-title":"Supplementation of arachidonic acid-enriched oil increases arachidonic acid contents in plasma phospholipids, but does not increase their metabolites and clinical parameters in Japanese healthy elderly individuals: A randomized controlled study","volume":"10","author":"Kakutani","year":"2011","journal-title":"Lipids Health Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1550-2783-4-21","article-title":"Effects of arachidonic acid supplementation on training adaptations in resistance-trained males","volume":"4","author":"Roberts","year":"2007","journal-title":"J. Int. Soc. Sports Nutr."},{"key":"ref_18","first-page":"521","article-title":"Increased arachidonate in lipids after administration to man: Effects on prostaglandin biosynthesis","volume":"18","author":"Seyberth","year":"1975","journal-title":"Clin. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1042\/CS20030182","article-title":"Effects of dietary supplementation with arachidonic acid on platelet and renal function in patients with cirrhosis","volume":"106","author":"Pantaleo","year":"2004","journal-title":"Clin. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/s11745-997-0055-7","article-title":"The effect of dietary arachidonic acid on platelet function, platelet fatty acid composition, and blood coagulation in humans","volume":"32","author":"Nelson","year":"1997","journal-title":"Lipids"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1126\/science.aar8486","article-title":"Evolutionary history and adaptation of a human pygmy population of Flores Island, Indonesia","volume":"361","author":"Tucci","year":"2018","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Richardson, T.G., Sanderson, E., Palmer, T.M., Ala-Korpela, M., Ference, B.A., Davey Smith, G., and Holmes, M.V. (2020). Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis. PLoS Med., 17.","DOI":"10.1371\/journal.pmed.1003062"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1002\/ana.25916","article-title":"Circulating Lipoprotein Lipids, Apolipoproteins and Ischemic Stroke","volume":"88","author":"Yuan","year":"2020","journal-title":"Ann. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1161\/CIRCGENETICS.113.000208","article-title":"Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium","volume":"7","author":"Guan","year":"2014","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","article-title":"The UK Biobank resource with deep phenotyping and genomic data","volume":"562","author":"Bycroft","year":"2018","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1038\/ng.2797","article-title":"Discovery and refinement of loci associated with lipid levels","volume":"45","author":"Willer","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3641","DOI":"10.1093\/hmg\/ddy271","article-title":"Meta-analysis of genome-wide association studies for height and body mass index in \u223c700000 individuals of European ancestry","volume":"27","author":"Yengo","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ajhg.2016.11.007","article-title":"Genome-wide Association Study Identifies 27 Loci Influencing Concentrations of Circulating Cytokines and Growth Factors","volume":"100","author":"Havulinna","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1002\/oby.23060","article-title":"The Role of Inflammatory Cytokines as Intermediates in the Pathway from Increased Adiposity to Disease","volume":"29","author":"Kalaoja","year":"2021","journal-title":"Obesity (Silver Spring)"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41586-018-0175-2","article-title":"Genomic atlas of the human plasma proteome","volume":"558","author":"Sun","year":"2018","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.ajhg.2018.09.009","article-title":"Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders","volume":"103","author":"Ligthart","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/s41588-018-0047-6","article-title":"Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases","volume":"50","author":"Kanai","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1038\/s41588-018-0205-x","article-title":"Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits","volume":"50","author":"Evangelou","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nature14177","article-title":"Genetic studies of body mass index yield new insights for obesity biology","volume":"518","author":"Locke","year":"2015","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1136\/jmedgenet-2018-105965","article-title":"Genome-wide association study identifies seven novel loci associating with circulating cytokines and cell adhesion molecules in Finns","volume":"56","author":"Sliz","year":"2019","journal-title":"J. Med. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4343","DOI":"10.2337\/db14-0731","article-title":"Genetic determinants of circulating interleukin-1 receptor antagonist levels and their association with glycemic traits","volume":"63","author":"Herder","year":"2014","journal-title":"Diabetes"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1016\/S0140-6736(12)60110-X","article-title":"The interleukin-6 receptor as a target for prevention of coronary heart disease: A mendelian randomisation analysis","volume":"379","author":"Swerdlow","year":"2012","journal-title":"Lancet"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1016\/S0140-6736(11)61931-4","article-title":"Interleukin-6 receptor pathways in coronary heart disease: A collaborative meta-analysis of 82 studies","volume":"379","author":"Sarwar","year":"2012","journal-title":"Lancet"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.ajhg.2012.05.009","article-title":"Genetic associations for activated partial thromboplastin time and prothrombin time, their gene expression profiles, and risk of coronary artery disease","volume":"91","author":"Tang","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1093\/hmg\/ddv454","article-title":"A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration","volume":"25","author":"Chasman","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1038\/ng.3396","article-title":"A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease","volume":"47","author":"Nikpay","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/s41588-018-0058-3","article-title":"Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes","volume":"50","author":"Malik","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_43","first-page":"1961","article-title":"Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: The role of the I2 statistic","volume":"45","author":"Bowden","year":"2016","journal-title":"Int. J. Epidemiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1002\/gepi.21758","article-title":"Mendelian randomization analysis with multiple genetic variants using summarized data","volume":"37","author":"Burgess","year":"2013","journal-title":"Genet. Epidemiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1007\/s10654-017-0255-x","article-title":"Interpreting findings from Mendelian randomization using the MR-Egger method","volume":"32","author":"Burgess","year":"2017","journal-title":"Eur. J. Epidemiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.ahj.2008.06.017","article-title":"Plasma fatty acid composition and incident heart failure in middle-aged adults: The Atherosclerosis Risk in Communities (ARIC) Study","volume":"156","author":"Yamagishi","year":"2008","journal-title":"Am. Heart J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1093\/ije\/dyy262","article-title":"An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings","volume":"48","author":"Sanderson","year":"2019","journal-title":"Int. J. Epidemiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4705","DOI":"10.1002\/sim.7492","article-title":"Extending the MR-Egger method for multivariable Mendelian randomization to correct for both measured and unmeasured pleiotropy","volume":"36","author":"Rees","year":"2017","journal-title":"Stat. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1093\/ije\/dyu005","article-title":"Sample size and power calculations in Mendelian randomization with a single instrumental variable and a binary outcome","volume":"43","author":"Burgess","year":"2014","journal-title":"Int. J. Epidemiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1056\/NEJMoa1206797","article-title":"Effects of dalcetrapib in patients with a recent acute coronary syndrome","volume":"367","author":"Schwartz","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.atherosclerosis.2020.02.002","article-title":"Apolipoprotein A-I concentrations and risk of coronary artery disease: A Mendelian randomization study","volume":"299","author":"Karjalainen","year":"2020","journal-title":"Atherosclerosis"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.3945\/ajcn.2009.28500","article-title":"Serum n-6 fatty acids and lipoprotein subclasses in middle-aged men: The population-based cross-sectional ERA-JUMP study","volume":"91","author":"Choo","year":"2010","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1016\/j.cca.2011.03.015","article-title":"Apolipoprotein A-I, apolipoprotein B, and apolipoprotein B\/apolipoprotein A-I ratio: Reference intervals compared with values in different pathophysiological conditions from the FINRISK 2007 study","volume":"412","author":"Sundvall","year":"2011","journal-title":"Clin. Chim. Acta"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S0021-9150(99)00374-3","article-title":"The effects of fatty acids on apolipoprotein B secretion by human hepatoma cells (HEP G2)","volume":"150","author":"Arrol","year":"2000","journal-title":"Atherosclerosis"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1007\/s11745-001-0831-4","article-title":"Influence of dietary supplementation with long-chain n-3 or n-6 polyunsaturated fatty acids on blood inflammatory cell populations and functions and on plasma soluble adhesion molecules in healthy adults","volume":"36","author":"Thies","year":"2001","journal-title":"Lipids"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1007\/s00125-019-05019-0","article-title":"Association of genetic variants related to plasma fatty acids with type 2 diabetes mellitus and glycaemic traits: A Mendelian randomisation study","volume":"63","author":"Yuan","year":"2020","journal-title":"Diabetologia"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.jclinepi.2019.05.005","article-title":"Effect measure modification conceptualized using selection diagrams as mediation by mechanisms of varying population-level relevance","volume":"113","author":"Lopez","year":"2019","journal-title":"J. Clin. Epidemiol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Schooling, C.M., Lopez, P.M., Yang, Z., Zhao, J.V., Au Yeung, S.L., and Huang, J. (2020). Use of multivariable Mendelian randomization to address biases due to competing risk before recruitment. Front. Genet.","DOI":"10.1101\/716621"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/5\/1489\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:54:31Z","timestamp":1760162071000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/5\/1489"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,28]]},"references-count":58,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["nu13051489"],"URL":"https:\/\/doi.org\/10.3390\/nu13051489","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,28]]}}}