Long-Chain Polysaturated Fatty Acid in Atrial Fibrillation–Associated Stroke: Lipidomic-GWAS Study

Youngae Jung; Beomsu Kim; Chi Kyung Kim; Hong-Hee Won; Su-Hyun Chae; Kyungmi Oh; Min-Jeong Shin; Geum-Sook Hwang; Woo-Keun Seo

doi:10.1055/a-2504-0903

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost
DOI: 10.1055/a-2504-0903

Stroke, Systemic or Venous Thromboembolism

Long-Chain Polysaturated Fatty Acid in Atrial Fibrillation–Associated Stroke: Lipidomic-GWAS Study

Authors

Youngae Jung^*

¹Integrated Metabolomics Research Group/Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea
Beomsu Kim^*

²Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Medical Center, Seoul, Republic of Korea
Chi Kyung Kim

³Department of Neurology, Korea University Guro Hospital, Korea University, Seoul, Republic of Korea
Hong-Hee Won

²Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Medical Center, Seoul, Republic of Korea
Su-Hyun Chae

¹Integrated Metabolomics Research Group/Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea

⁴Department of Chemistry, Sungkyunkwan University, Suwon, Republic of Korea
Kyungmi Oh

³Department of Neurology, Korea University Guro Hospital, Korea University, Seoul, Republic of Korea
Min-Jeong Shin

⁵Department of Public Health Sciences, Korea University, Seoul, Republic of Korea
Geum-Sook Hwang

¹Integrated Metabolomics Research Group/Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea

⁶College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea
Woo-Keun Seo

⁷Department of Neurology, Samsung Medical Center, Sungkyunkwan University and Department of Digital Health, SAIHST, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

Abstract

Background and Purpose

This study aimed to explore the relationship between lipidomic domains, particularly free fatty acids (FFAs), and the presence of atrial fibrillation (AF) in patients with acute stroke, and to identify mechanisms of AF-associated stroke through genetic studies.

Methods

A total of 483 stroke patients without AF (n = 391) and with AF (n = 92) were selected from a prospectively collected stroke registry. Lipidomic profiling was conducted, and the lipid components associated with AF were explored using fold-change analyses and clustering. Genotyping was conducted through trait comparison. Colocalization was also performed.

Results

Among the lipidomic domains, the free fatty acid (FFA) class was positively associated with AF. Long-chain fatty acids with 14 to 24 carbons and unsaturated FFAs distinguished AF. Clustering analysis based on FFAs revealed differences in AF proportion across groups. Genome-wide association study (GWAS) identified two loci associated with clustered groups of FFA metabolites: near MIR548F3 associated with FFA 20:1, FFA 20:2, FFA 22:5, and FFA 22:6; and near RPL37A associated with FFA 22:5 and FFA 22:6. These loci were associated with increased fibrinogen levels. In the GWAS for the FFA metabolite, quantitative trial locus analysis, loci near rs28456 and rs3770088, and FFA 20:4-QTLs were co-localized with the eQTLs of FADS2, a gene involved in the peroxisome proliferator-activated receptor gamma-related signaling pathway, in the whole blood, left ventricle, and atrial appendage tissue.

Conclusion

Elevated FFA levels, especially those of long-chain unsaturated FFAs, are strongly associated with AF-associated stroke. This relationship is regulated by the peroxisome proliferator-activated receptor (PPAR) gamma-related signaling pathway.

Keywords

atrial fibrillation - stroke - lipidomics - genome-wide association study - free fatty acids - peroxisome proliferator-activated receptor gamma

Full Text

References

References
1 GBD 2017 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018; 392 (10159): 1859-1922
2 Stroke Collaborators GBD. GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol 2021; 20 (10) 795-820
3 Ferro JM. Cardioembolic stroke: an update. Lancet Neurol 2003; 2 (03) 177-188
4 Seo WK, Jung JM, Kim JH, Koh SB, Bang OY, Oh K. Free fatty acid is associated with thrombogenicity in cardioembolic stroke. Cerebrovasc Dis 2017; 44 (3-4): 160-168
5 Chung JW, Seo WK, Kim GM, Chung CS, Lee KH, Bang OY. Free fatty acid as a determinant of ischemic lesion volume in nonarterial-origin embolic stroke. J Neurol Sci 2017; 382: 116-121
6 Choi JY, Jung JM, Kwon DY. et al. Free fatty acid as an outcome predictor of atrial fibrillation-associated stroke. Ann Neurol 2016; 79 (02) 317-325
7 Choi JY, Kim JS, Kim JH, Oh K, Koh SB, Seo WK. High free fatty acid level is associated with recurrent stroke in cardioembolic stroke patients. Neurology 2014; 82 (13) 1142-1148
8 Seo WK, Kim J, Kim YH. et al. Elevated free fatty acid is associated with cardioembolic stroke subtype. Can J Neurol Sci 2011; 38 (06) 874-879
9 Eun MY, Seo WK, Lee J. et al. Age-dependent predictors for recurrent stroke: the paradoxical role of triglycerides. Eur Neurol 2013; 69 (03) 171-178
10 Lee AY, Levine MN, Baker RI. et al; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349 (02) 146-153
11 Adams Jr HP, Bendixen BH, Kappelle LJ. et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24 (01) 35-41
12 Manichaikul A, Mychaleckyj JC, Rich SS, Daly K, Sale M, Chen WM. Robust relationship inference in genome-wide association studies. Bioinformatics 2010; 26 (22) 2867-2873
13 Das S, Forer L, Schönherr S. et al. Next-generation genotype imputation service and methods. Nat Genet 2016; 48 (10) 1284-1287
14 Bi W, Zhou W, Dey R, Mukherjee B, Sampson JN, Lee S. Efficient mixed model approach for large-scale genome-wide association studies of ordinal categorical phenotypes. Am J Hum Genet 2021; 108 (05) 825-839
15 GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science 2020; 369 (6509): 1318-1330
16 Giambartolomei C, Vukcevic D, Schadt EE. et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet 2014; 10 (05) e1004383
17 Yang J, Ferreira T, Morris AP. et al; Genetic Investigation of ANthropometric Traits (GIANT) Consortium, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat Genet 2012; 44 (04) 369-375 , S1–S3
18 Zheng J, Haberland V, Baird D. et al. Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases. Nat Genet 2020; 52 (10) 1122-1131
19 Nakamura MT, Yudell BE, Loor JJ. Regulation of energy metabolism by long-chain fatty acids. Prog Lipid Res 2014; 53: 124-144
20 Wei XJ, Han M, Wei GC, Duan CH. Prognostic value of cerebrospinal fluid free fatty acid levels in patients with acute ischemic stroke. Front Hum Neurosci 2015; 9: 402
21 Sun GJ, Ding SC, Ling WY, Wang F, Yang XP. Cerebrospinal fluid free fatty acid levels are associated with stroke subtypes and severity in Chinese patients with acute ischemic stroke. World Neurosurg 2015; 84 (05) 1299-1304
22 Seo WK, Kang SH, Jung JM, Choi JY, Oh K. Novel composite score to predict atrial fibrillation in acute stroke patients: AF predicting score in acute stroke. Int J Cardiol 2016; 209: 184-189
23 Duan XX, Zhang GP, Wang XB. et al. Elevated serum and cerebrospinal fluid free fatty acid levels are associated with unfavorable functional outcome in subjects with acute ischemic stroke. Mol Neurobiol 2017; 54 (03) 1677-1683
24 Hierons SJ, Marsh JS, Wu D, Blindauer CA, Stewart AJ. The interplay between non-esterified fatty acids and plasma zinc and its influence on thrombotic risk in obesity and type 2 diabetes. Int J Mol Sci 2021; 22 (18) 10140
25 Ahmed NS, Lopes Pires ME, Taylor KA, Pugh N. Agonist-evoked increases in intra-platelet zinc couple to functional responses. Thromb Haemost 2019; 119 (01) 128-139
26 Bal W, Sokołowska M, Kurowska E, Faller P. Binding of transition metal ions to albumin: sites, affinities and rates. Biochim Biophys Acta 2013; 1830 (12) 5444-5455
27 Albert CM, Cook NR, Pester J. et al. Effect of marine omega-3 fatty acid and vitamin D supplementation on incident atrial fibrillation: a randomized clinical trial. JAMA 2021; 325 (11) 1061-1073
28 Nicholls SJ, Lincoff AM, Garcia M. et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA 2020; 324 (22) 2268-2280
29 Bhatt DL, Steg PG, Miller M. et al; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019; 380 (01) 11-22
30 Kalstad AA, Myhre PL, Laake K. et al; OMEMI Investigators. Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: a randomized, controlled trial. Circulation 2021; 143 (06) 528-539
31 Lombardi M, Carbone S, Del Buono MG. et al. Omega-3 fatty acids supplementation and risk of atrial fibrillation: an updated meta-analysis of randomized controlled trials. Eur Heart J Cardiovasc Pharmacother 2021; 7 (04) e69-e70
32 Chung HK, Cho Y, Do HJ, Oh K, Seo WK, Shin MJ. Plasma phospholipid arachidonic acid and lignoceric acid are associated with the risk of cardioembolic stroke. Nutr Res 2015; 35 (11) 1001-1008
33 Fatkin D, Cox CD, Martinac B. Fishing for links between omega-3 fatty acids and atrial fibrillation. Circulation 2022; 145 (14) 1037-1039
34 Liu HJ, Liao HH, Yang Z, Tang QZ. Peroxisome proliferator-activated receptor-gamma is critical to cardiac fibrosis. PPAR Res 2016; 2016: 2198645
35 Shimano M, Tsuji Y, Inden Y. et al. Pioglitazone, a peroxisome proliferator-activated receptor-gamma activator, attenuates atrial fibrosis and atrial fibrillation promotion in rabbits with congestive heart failure. Heart Rhythm 2008; 5 (03) 451-459
36 Chen HX, Li MY, Jiang YY. et al. Role of PPAR pathway in atrial fibrillation associated with heart valvular disease: transcriptomics and proteomics in the human atrial tissue. Signal Transduct Target Ther 2020; 05 (01) 4

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