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Open Access 01-12-2020 | Stroke | Research

Roles for circulating polyunsaturated fatty acids in ischemic stroke and modifiable factors: a Mendelian randomization study

Authors: Tonghui Yuan, Shucheng Si, Yunxia Li, Wenchao Li, Xiaolu Chen, Congcong Liu, Jiqing Li, Bojie Wang, Lei Hou, Yanxun Liu, Fuzhong Xue

Published in: Nutrition Journal | Issue 1/2020

Abstract

Background

Available data about the effects of circulating polyunsaturated fatty acids (PUFAs) on ischemic stroke (IS) and its main risk factors remains limited and conflicting. Therefore, we conducted Mendelian randomization (MR) to assess whether genetically predicted PUFA affected IS, lipids and blood pressure (BP).

Methods

Genetic instruments associated with IS were derived from ISGC Consortium (n = 29,633), with lipids were derived from GLGC(n = 188,577), with BP were derived from Neale Lab(n = 337,000). The inverse-variance weighted method was the main analysis to estimate the effect of exposure on outcome. Sensitivity analyses included principal components analysis, MR-Egger, weighted median, and weighted mode.

Results

Per SD increases in serum α-linolenic acid (ALA) were associated with lower IS risk, with odd ratio (OR) of 0.867(0.782,0.961), arachidonic acid (AA) were associated with higher IS risk (OR: 1.053(1.014,1.094)). Likewise, Per SD increases in ALA were associated with the lower-level low-density lipoprotein cholesterol(LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC) (β:-0.122(− 0.144, − 0.101), − 0.159(− 0.182, − 0.135), − 0.148(− 0.171, − 0.126), respectively), AA were associated with the higher-level of LDL-C, HDL-C and TC (β:0.045(0.034,0.056), 0.059(0.050,0.067), 0.055(0.046,0.063), respectively). Linoleic acid (LA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) had little or no association with IS, lipids or BP at Bonferroni-corrected significance. Different analytic methods supported these findings. The intercept test of MR-Egger implied no pleiotropy.

Conclusions

High-level plasma ALA was protective for IS but AA was the opposite. LA, EPA, DHA, and DPA had no effects on IS.

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Joseph P, Leong D, McKee M, Anand SS, Schwalm JD, Teo K, et al. Reducing the global burden of cardiovascular disease, part 1: the epidemiology and risk factors. Circ Res. 2017;121:677–94 https://doi.org/10.1161/CIRCRESAHA.117.308903.PubMed

Buddeke J, Bots ML, van Dis I, Visseren FL, Hollander M, Schellevis FG, et al. Comorbidity in patients with cardiovascular disease in primary care: a cohort study with routine healthcare data. Br J Gen Pract. 2019;69:e398–406. https://doi.org/10.3399/bjgp19X702725.PubMedPubMedCentral

GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1459–544. https://doi.org/10.1016/S0140-6736(16)31012-1.

O'Donnell MJ, Chin SL, Rangarajan S, Xavier D, Liu L, Zhang H, et al. Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study. Lancet. 2016; 388: 761–775. https://doi.org/10.1016/S0140-6736(16)30506-2.

Libby P, Buring JE, Badimon L, Hansson GK, Deanfield J, Bittencourt MS, et al. Atherosclerosis. Nat Rev Dis Primers. 2019;5:56 https://doi.org/10.1038/s41572-019-0106-z.PubMed

Herrington W, Lacey B, Sherliker P, Armitage J, Lewington S. Epidemiology of atherosclerosis and the potential to reduce the global burden of Atherothrombotic disease. Circ Res. 2016;118:535–46 https://doi.org/10.1161/CIRCRESAHA.115.307611.PubMed

Ridker PM. Testing the inflammatory hypothesis of atherothrombosis: scientific rationale for the cardiovascular inflammation reduction trial (CIRT). J Thromb Haemost. 2009;7(Suppl 1):332–9 https://doi.org/10.1111/j.1538-7836.2009.03404.x.PubMed

Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868–74 https://doi.org/10.1038/nature01323.PubMed

Geovanini GR, Libby P. Atherosclerosis and inflammation: overview and updates. Clin Sci (Lond). 2018;132:1243–52 https://doi.org/10.1042/CS20180306.

10.

Abdelhamid AS, Brown TJ, Brainard JS, Biswas P, Thorpe GC, Moore HJ, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018;11:D3177 https://doi.org/10.1002/14651858.CD003177.pub4.

11.

Hooper L, Al-Khudairy L, Abdelhamid AS, Rees K, Brainard JS, Brown TJ, et al. Omega-6 fats for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018;11:D11094 https://doi.org/10.1002/14651858.CD011094.pub4.

12.

Saini RK, Keum YS. Omega-3 and omega-6 polyunsaturated fatty acids: dietary sources, metabolism, and significance - a review. Life Sci. 2018;203:255–67 https://doi.org/10.1016/j.lfs.2018.04.049.PubMed

13.

Patterson E, Wall R, Fitzgerald GF, Ross RP, Stanton C. Health implications of high dietary omega-6 polyunsaturated fatty acids. J Nutr Metab. 2012;2012:539426 https://doi.org/10.1155/2012/539426.PubMedPubMedCentral

14.

Marklund M, Wu J, Imamura F, Del GL, Fretts A, de Goede J, et al. Biomarkers of dietary Omega-6 fatty acids and incident cardiovascular disease and mortality. Circulation. 2019;139:2422–36 https://doi.org/10.1161/CIRCULATIONAHA.118.038908.PubMedPubMedCentral

15.

Surveillance report 2018 – Cardiovascular disease: risk assessment and reduction, including lipid modification (2014) NICE guideline CG181. London: National Institute for Health and Care Excellence (UK); 2018.

16.

Papanikolaou Y, Brooks J, Reider C, Fulgoni VR. U.S. adults are not meeting recommended levels for fish and omega-3 fatty acid intake: results of an analysis using observational data from NHANES 2003–2008. Nutr J. 2014;13:31 https://doi.org/10.1186/1475-2891-13-31.PubMedPubMedCentral

17.

Xun P, Qin B, Song Y, Nakamura Y, Kurth T, Yaemsiri S, et al. Fish consumption and risk of stroke and its subtypes: accumulative evidence from a meta-analysis of prospective cohort studies. Eur J Clin Nutr. 2012;66:1199–207 https://doi.org/10.1038/ejcn.2012.133.PubMedPubMedCentral

18.

He K, Rimm EB, Merchant A, Rosner BA, Stampfer MJ, Willett WC, et al. Fish consumption and risk of stroke in men. JAMA. 2002;288:3130–6 https://doi.org/10.1001/jama.288.24.3130.PubMed

19.

Iso H, Rexrode KM, Stampfer MJ, Manson JE, Colditz GA, Speizer FE, et al. Intake of fish and omega-3 fatty acids and risk of stroke in women. JAMA. 2001;285:304–12 https://doi.org/10.1001/jama.285.3.304.PubMed

20.

American Heart Association. Fish and Omega-3 Fatty Acids. https://www.heart.org/en/healthy-living/healthy-eating/eat-smart/fats/fish-and-omega-3-fatty-acids. Accessed 06 Jan 2020.

21.

Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and Cancer. N Engl J Med. 2019;380:23–32 https://doi.org/10.1056/NEJMoa1811403.PubMed

22.

Simonetto M, Infante M, Sacco RL, Rundek T, Della-Morte D A Novel Anti-Inflammatory Role of Omega-3 PUFAs in Prevention and Treatment of Atherosclerosis and Vascular Cognitive Impairment and Dementia. Nutrients. 2019; 11:https://doi.org/10.3390/nu11102279.

23.

Takata Y, Zhang X, Li H, Gao YT, Yang G, Gao J, et al. Fish intake and risks of total and cause-specific mortality in 2 population-based cohort studies of 134,296 men and women. Am J Epidemiol. 2013;178:46–57 https://doi.org/10.1093/aje/kws584.PubMedPubMedCentral

24.

Maki KC, Eren F, Cassens ME, Dicklin MR, Davidson MH. Omega-6 polyunsaturated fatty acids and Cardiometabolic health: current evidence, controversies, and research gaps. Adv Nutr. 2018;9:688–700 https://doi.org/10.1093/advances/nmy038.PubMedPubMedCentral

25.

Laursen A, Dahm CC, Johnsen SP, Schmidt EB, Overvad K, Jakobsen MU. Adipose tissue fatty acids present in dairy fat and risk of stroke: the Danish diet, Cancer and health cohort. Eur J Nutr. 2019;58:529–39 https://doi.org/10.1007/s00394-018-1608-2.PubMed

26.

Daneshmand R, Kurl S, Tuomainen TP, Virtanen JK. Associations of serum n-3 and n-6 PUFA and hair mercury with the risk of incident stroke in men: the Kuopio Ischaemic heart disease risk factor study (KIHD). Br J Nutr. 2016;115:1851–9 https://doi.org/10.1017/S0007114516000982.PubMed

27.

Wu JH, Lemaitre RN, King IB, Song X, Psaty BM, Siscovick DS, et al. Circulating omega-6 polyunsaturated fatty acids and total and cause-specific mortality: the cardiovascular health study. Circulation. 2014;130:1245–53 https://doi.org/10.1161/CIRCULATIONAHA.114.011590.PubMedPubMedCentral

28.

Yaemsiri S, Sen S, Tinker LF, Robinson WR, Evans RW, Rosamond W, et al. Serum fatty acids and incidence of ischemic stroke among postmenopausal women. Stroke. 2013;44:2710–7 https://doi.org/10.1161/STROKEAHA.111.000834.PubMedPubMedCentral

29.

Iso H, Sato S, Umemura U, Kudo M, Koike K, Kitamura A, et al. Linoleic acid, other fatty acids, and the risk of stroke. Stroke. 2002;33:2086–93 https://doi.org/10.1161/01.str.0000023890.25066.50.PubMed

30.

Zhao JV, Schooling CM. Effect of linoleic acid on ischemic heart disease and its risk factors: a Mendelian randomization study. BMC Med. 2019;17:61 https://doi.org/10.1186/s12916-019-1293-x.PubMedPubMedCentral

31.

Yuan S, Larsson SC Plasma Phospholipid Fatty Acids and Risk of Atrial Fibrillation: A Mendelian Randomization Study. Nutrients. 2019; 11:https://doi.org/10.3390/nu11071651.

32.

Liao LZ, Li WD, Liu Y, Li JP, Zhuang XD, Liao XX Exploring the causal pathway from omega-6 levels to coronary heart disease: A network Mendelian randomization study. Nutr Metab Cardiovasc Dis. 2019:https://doi.org/10.1016/j.numecd.2019.09.013.

33.

Smith GD, Ebrahim S. Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32:1–22 https://doi.org/10.1093/ije/dyg070.PubMed

34.

Valdes-Marquez E, Parish S, Clarke R, Stari T, Worrall BB, Hopewell JC. Relative effects of LDL-C on ischemic stroke and coronary disease: a Mendelian randomization study. Neurology. 2019;92:e1176–87 https://doi.org/10.1212/WNL.0000000000007091.PubMedPubMedCentral

35.

Hindy G, Engstrom G, Larsson SC, Traylor M, Markus HS, Melander O, et al. Role of blood lipids in the development of ischemic stroke and its subtypes: a Mendelian randomization study. Stroke. 2018;49:820–7 https://doi.org/10.1161/STROKEAHA.117.019653.PubMedPubMedCentral

36.

Peters SA, Singhateh Y, Mackay D, Huxley RR, Woodward M. Total cholesterol as a risk factor for coronary heart disease and stroke in women compared with men: a systematic review and meta-analysis. Atherosclerosis. 2016;248:123–31 https://doi.org/10.1016/j.atherosclerosis.2016.03.016.PubMed

37.

Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, Thompson A, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302:1993–2000 https://doi.org/10.1001/jama.2009.1619.PubMed

38.

Bowden J, Davey SG, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through egger regression. Int J Epidemiol. 2015;44:512–25 https://doi.org/10.1093/ije/dyv080.PubMedPubMedCentral

39.

Guan W, Steffen BT, Lemaitre RN, Wu J, Tanaka T, Manichaikul A, et al. Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium. Circ Cardiovasc Genet. 2014;7:321–31 https://doi.org/10.1161/CIRCGENETICS.113.000208.PubMedPubMedCentral

40.

Lemaitre RN, Tanaka T, Tang W, Manichaikul A, Foy M, Kabagambe EK, et al. Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE consortium. PLoS Genet. 2011;7:e1002193 https://doi.org/10.1371/journal.pgen.1002193.PubMedPubMedCentral

41.

LDlink. https://ldlink.n?tab=snpclip/?tab=snpclip. Accessed 12 Nov 2019.

42.

Burgess S, Zuber V, Valdes-Marquez E, Sun BB, Hopewell JC. Mendelian randomization with fine-mapped genetic data: choosing from large numbers of correlated instrumental variables. Genet Epidemiol. 2017;41:714–25 https://doi.org/10.1002/gepi.22077.PubMedPubMedCentral

43.

Bowden J, Del GMF, Minelli C, Davey SG, Sheehan NA, Thompson JR. Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-egger regression: the role of the I2 statistic. Int J Epidemiol. 2016;45:1961–74 https://doi.org/10.1093/ije/dyw220.PubMedPubMedCentral

44.

Ettner SL Measuring the human cost of a weak economy: does unemployment lead to alcohol abuse? Soc Sci Med 1997; 44: 251–260. https://doi.org/10.1016/s0277-9536(96)00160-8.

45.

Malik R, Traylor M, Pulit SL, Bevan S, Hopewell JC, Holliday EG, et al. Low-frequency and common genetic variation in ischemic stroke: the METASTROKE collaboration. Neurology. 2016;86:1217–26 https://doi.org/10.1212/WNL.0000000000002528.PubMedPubMedCentral

46.

Willer CJ, Schmidt EM, Sengupta S, Peloso GM, Gustafsson S, Kanoni S, et al. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45:1274–83 https://doi.org/10.1038/ng.2797.PubMedPubMedCentral

47.

Neale lab. http://www.nealelab.is/uk-biobank/. Accessed 12 Nov 2019.:.

48.

Yamagishi K, Nettleton JA, Folsom AR. Plasma fatty acid composition and incident heart failure in middle-aged adults: the atherosclerosis risk in communities (ARIC) study. Am Heart J. 2008;156:965–74 https://doi.org/10.1016/j.ahj.2008.06.017.PubMedPubMedCentral

49.

Hartwig FP, Davey SG, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol. 2017;46:1985–98 https://doi.org/10.1093/ije/dyx102.PubMedPubMedCentral

50.

Bowden J, Davey SG, Haycock PC, Burgess S. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40:304–14 https://doi.org/10.1002/gepi.21965.PubMedPubMedCentral

51.

Kamat MA, Blackshaw JA, Young R, Surendran P, Burgess S, Danesh J, et al. PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations. Bioinformatics. 2019;35:4851–3 https://doi.org/10.1093/bioinformatics/btz469.PubMedPubMedCentral

52.

Veno SK, Schmidt EB, Jakobsen MU, Lundbye-Christensen S, Bach FW, Overvad K. Substitution of linoleic acid for other macronutrients and the risk of ischemic stroke. Stroke. 2017;48:3190–5 https://doi.org/10.1161/STROKEAHA.117.017935.PubMed

53.

Johnson GH, Fritsche K Effect of dietary linoleic acid on markers of inflammation in healthy persons: a systematic review of randomized controlled trials. J Acad Nutr Diet. 2012; 112: 1029–1041, 1041. https://doi.org/10.1016/j.jand.2012.03.029.

54.

De Goede J, Verschuren WM, Boer JM, Kromhout D, Geleijnse JM. N-6 and n-3 fatty acid cholesteryl esters in relation to incident stroke in a Dutch adult population: a nested case-control study. Nutr Metab Cardiovasc Dis. 2013;23:737–43 https://doi.org/10.1016/j.numecd.2012.03.001.PubMed

55.

Bjermo H, Iggman D, Kullberg J, Dahlman I, Johansson L, Persson L, et al. Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial. Am J Clin Nutr. 2012;95:1003–12 https://doi.org/10.3945/ajcn.111.030114.PubMed

56.

de Goede J, Geleijnse JM, Boer JM, Kromhout D, Verschuren WM. Linoleic acid intake, plasma cholesterol and 10-year incidence of CHD in 20,000 middle-aged men and women in the Netherlands. Br J Nutr. 2012;107:1070–6 https://doi.org/10.1017/S0007114511003837.PubMed

57.

Jang H, Park K. Omega-3 and omega-6 polyunsaturated fatty acids and metabolic syndrome: a systematic review and meta-analysis. Clin Nutr. 2020;39:765–73 https://doi.org/10.1016/j.clnu.2019.03.032.PubMed

58.

Silva FP, Carla IA, Marcelino G, Maiara LCC, de Cassia FK, de Cassia AGR, et al. Fatty Acids Consumption: The Role Metabolic Aspects Involved in Obesity and Its Associated Disorders. Nutrients. 2017:9 https://doi.org/10.3390/nu9101158.

59.

Carracedo M, Artiach G, Arnardottir H, Back M. The resolution of inflammation through omega-3 fatty acids in atherosclerosis, intimal hyperplasia, and vascular calcification. Semin Immunopathol. 2019;41:757–66 https://doi.org/10.1007/s00281-019-00767-y.PubMedPubMedCentral

60.

Bosch J, Gerstein HC, Dagenais GR, Diaz R, Dyal L, Jung H, et al. N-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012;367:309–18 https://doi.org/10.1056/NEJMoa1203859.PubMed

61.

Eslick GD, Howe PR, Smith C, Priest R, Bensoussan A. Benefits of fish oil supplementation in hyperlipidemia: a systematic review and meta-analysis. Int J Cardiol. 2009;136:4–16 https://doi.org/10.1016/j.ijcard.2008.03.092.PubMed

62.

Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J. Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review. Atherosclerosis. 2006;189:19–30 https://doi.org/10.1016/j.atherosclerosis.2006.02.012.PubMed

63.

Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, Barton J, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018;379:1540–50 https://doi.org/10.1056/NEJMoa1804989.PubMed

64.

Siscovick DS, Barringer TA, Fretts AM, Wu JH, Lichtenstein AH, Costello RB, et al. Omega-3 polyunsaturated fatty acid (fish oil) supplementation and the prevention of clinical cardiovascular disease: a science advisory from the American Heart Association. Circulation. 2017;135:e867–84 https://doi.org/10.1161/CIR.0000000000000482.PubMedPubMedCentral

65.

Roncaglioni MC, Tombesi M, Avanzini F, Barlera S, Caimi V, Longoni P, et al. N-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 2013;368:1800–8 https://doi.org/10.1056/NEJMoa1205409.PubMed

66.

Galan P, Kesse-Guyot E, Czernichow S, Briancon S, Blacher J, Hercberg S. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. BMJ. 2010;341:c6273 https://doi.org/10.1136/bmj.c6273.PubMedPubMedCentral

Title: Roles for circulating polyunsaturated fatty acids in ischemic stroke and modifiable factors: a Mendelian randomization study
Authors: Tonghui Yuan
Shucheng Si
Yunxia Li
Wenchao Li
Xiaolu Chen
Congcong Liu
Jiqing Li
Bojie Wang
Lei Hou
Yanxun Liu
Fuzhong Xue
Publication date: 01-12-2020
Publisher: BioMed Central
Keyword: Stroke
Published in: Nutrition Journal / Issue 1/2020
Electronic ISSN: 1475-2891
DOI: https://doi.org/10.1186/s12937-020-00582-4

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