Lipid Metabolism Genes in Stroke Pathogenesis: The Atherosclerosis

Author(s): Yit-Lai Chow, Lai Kuan Teh, Loh Huey Chyi, Li Fang Lim, Chin Chu Yee, Loo Keat Wei*

Journal Name: Current Pharmaceutical Design

Volume 26 , Issue 34 , 2020

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Stroke is the second leading cause of death and a major cause of disability worldwide. Both modifiable and non-modifiable risk factors can affect the occurrence of ischemic stroke at varying degrees. Among them, atherosclerosis has been well-recognized as one of the main culprits for the rising incidence of stroke-related mortality. Hence, the current review aimed to summarize the prominent role of lipid metabolism genes such as PCSK9, ApoB, ApoA5, ApoC3, ApoE, and ABCA1 in mediating ischemic stroke occurrence.

Keywords: Lipids, gene, stroke, metabolism, PCSK9, ApoB, ApoA5, ApoC3, ApoE, ABCA1.

Wei LK, Au A, Menon S, Gan SH, Griffiths LR. Clinical relevance of MTHFR, eNOS, ACE, and ApoE gene polymorphisms and serum vitamin profile among Malay patients with ischemic stroke. J Stroke Cerebrovasc Dis 2015; 24(9): 2017-25.
[] [PMID: 26187788]
Amarenco P, Bogousslavsky J, Caplan LR, Donnan GA, Hennerici MG. Classification of stroke subtypes. Cerebrovasc Dis 2009; 27(5): 493-501.
[] [PMID: 19342825]
Loo KW, Gan SH. Burden of stroke in Malaysia. Int J Stroke 2012; 7(2): 165-7.
[] [PMID: 22264370]
Wei LK, Au A, Teh LK, Lye HS. Recent advances in the genetics of hypertension Hypertension: from basic research to clinical practice 2016; 561-81.
Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res 2014; 114(12): 1852-66.
[] [PMID: 24902970]
Turan Y, Kozan A, Başkaya MK. Management of lipid metabolism Primer on cerebrovascular diseases 2nd ed. 2017; 870-3.
Durrington PN. Triglycerides are more important in atherosclerosis than epidemiology has suggested. Atherosclerosis 1998; 141(Suppl. 1): S57-62.
[] [PMID: 9888644]
Murphy HC, Burns SP, White JJ, Bell JD, Iles RA. Investigation of human low-density lipoprotein by (1)H nuclear magnetic resonance spectroscopy: mobility of phosphatidylcholine and sphingomyelin headgroups characterizes the surface layer. Biochemistry 2000; 39(32): 9763-70.
[] [PMID: 10933793]
Segrest JP, Garber DW, Brouillette CG, Harvey SC, Anantharamaiah GM. The amphipathic alpha helix: a multifunctional structural motif in plasma apolipoproteins. Adv Protein Chem 1994; 45: 303-69.
[] [PMID: 8154372]
Schmidt K, Noureen A, Kronenberg F, Utermann G. Structure, function, and genetics of lipoprotein (a). J Lipid Res 2016; 57(8): 1339-59.
[] [PMID: 27074913]
Orsó E, Schmitz G. Lipoprotein(a) and its role in inflammation, atherosclerosis and malignancies. Clin Res Cardiol Suppl 2017; 12(Suppl. 1): 31-7.
[] [PMID: 28188431]
Hussain MM. Intestinal lipid absorption and lipoprotein formation. Curr Opin Lipidol 2014; 25(3): 200-6.
[] [PMID: 24751933]
Kindel T, Lee DM, Tso P. The mechanism of the formation and secretion of chylomicrons. Atheroscler Suppl 2010; 11(1): 11-6.
[] [PMID: 20493784]
Xiao C, Stahel P, Lewis GF. Regulation of chylomicron secretion: focus on post assembly mechanisms. Cell Mol Gastroenterol Hepatol 2019; 7(3): 487-501.
[] [PMID: 30819663]
Tiwari S, Siddiqi SA. Intracellular trafficking and secretion of VLDL. Arterioscler Thromb Vasc Biol 2012; 32(5): 1079-86.
[] [PMID: 22517366]
Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol 2009; 29(4): 431-8.
[] [PMID: 19299327]
Wang S, Smith JD. ABCA1 and nascent HDL biogenesis. Biofactors 2014; 40(6): 547-54.
[] [PMID: 25359426]
Wang B, Tontonoz P. Liver X receptors in lipid signalling and membrane homeostasis. Nat Rev Endocrinol 2018; 14(8): 452-63.
[] [PMID: 29904174]
Hu YW, Wang Q, Ma X, et al. TGF-beta1 up-regulates expression of ABCA1, ABCG1 and SR-BI through liver X receptor alpha signaling pathway in THP-1 macrophage-derived foam cells. J Atheroscler Thromb 2010; 17(5): 493-502.
[] [PMID: 20057170]
Cimmino G, Ibanez B, Vilahur G, et al. Up-regulation of reverse cholesterol transport key players and rescue from global inflammation by ApoA-I(Milano). J Cell Mol Med 2009; 13(9B): 3226-35.
[] [PMID: 19120689]
Goldstein JL, DeBose-Boyd RA, Brown MS. Protein sensors for membrane sterols. Cell 2006; 124(1): 35-46.
[] [PMID: 16413480]
Mineo C. Lipoprotein receptor signaling in atherosclerosis. Cardiovasc Res 2019; 116(7): 1254-74.
Eberlé D, Hegarty B, Bossard P, Ferré P, Foufelle F. SREBP transcription factors: master regulators of lipid homeostasis. Biochimie 2004; 86(11): 839-48.
[] [PMID: 15589694]
DeBose-Boyd RA, Ye J. SREBPs in lipid metabolism, insuling signaling, and beyond. Trends Biochem Sci 2018; 43(5): 358-68.
[] [PMID: 29500098]
Lambert G, Ancellin N, Charlton F, et al. Plasma PCSK9 concentrations correlate with LDL and total cholesterol in diabetic patients and are decreased by fenofibrate treatment. Clin Chem 2008; 54(6): 1038-45.
[] [PMID: 18436719]
Lagace TA. PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells. Curr Opin Lipidol 2014; 25(5): 387-93.
[] [PMID: 25110901]
Au A, Griffiths LR, Cheng KK, Wee Kooi C, Irene L, Keat Wei L. The influence of OLR1 and PCSK9 gene polymorphisms on ischemic stroke: evidence from a meta-analysis. Sci Rep 2015; 5: 18224.
[] [PMID: 26666837]
Stoekenbroek RM, Kastelein JJ, Huijgen R. PCSK9 inhibition: the way forward in the treatment of dyslipidemia. BMC Med 2015; 13(1): 258.
[] [PMID: 26456772]
Varret M, Rabès JP, Saint-Jore B, et al. A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32. Am J Hum Genet 1999; 64(5): 1378-87.
[] [PMID: 10205269]
Au A. Metabolomics and lipidomics of ischemic stroke Advances in clinical chemistry Elsevier 2018; 85: 31-9.
Au A, Griffiths LR, Irene L, Kooi CW, Wei LK. The impact of APOA5, APOB, APOC3 and ABCA1 gene polymorphisms on ischemic stroke: Evidence from a meta-analysis. Atherosclerosis 2017; 265: 60-70.
[] [PMID: 28865324]
Chiodini BD, Barlera S, Franzosi MG, Beceiro VL, Introna M, Tognoni G. APO B gene polymorphisms and coronary artery disease: a meta-analysis. Atherosclerosis 2003; 167(2): 355-66.
[] [PMID: 12818419]
Nikolajevic Starcevic J, Santl Letonja M, Praznikar ZJ, Makuc J, Vujkovac AC, Petrovic D. Polymorphisms XbaI (rs693) and EcoRI (rs1042031) of the ApoB gene are associated with carotid plaques but not with carotid intima-media thickness in patients with diabetes mellitus type 2. Vasa 2014; 43(3): 171-80.
[] [PMID: 24797048]
Boekholdt SM, Peters RJ, Fountoulaki K, Kastelein JJ, Sijbrands EJ. Molecular variation at the apolipoprotein B gene locus in relation to lipids and cardiovascular disease: a systematic metaanalysis. Hum Genet 2003; 113(5): 417-25.
[] [PMID: 12942366]
Zhou F, Guo T, Zhou L, Zhou Y, Yu D. Variants in the APOB gene was associated with Ischemic Stroke susceptibility in Chinese Han male population. Oncotarget 2017; 9(2): 2249-54.
[] [PMID: 29416768]
Turner PR, Talmud PJ, Visvikis S, Ehnholm C, Tiret L. DNA polymorphisms of the apoprotein B gene are associated with altered plasma lipoprotein concentrations but not with perceived risk of cardiovascular disease: European Atherosclerosis Research Study. Atherosclerosis 1995; 116(2): 221-34.
[] [PMID: 7575777]
Elosua R, Ordovas JM, Cupples LA, et al. Variants at the APOA5 locus, association with carotid atherosclerosis, and modification by obesity: the Framingham Study. J Lipid Res 2006; 47(5): 990-6.
[] [PMID: 16474174]
Chen H, Ding S, Zhou M, et al. Association of rs662799 in APOA5 with CAD in Chinese Han population. BMC Cardiovasc Disord 2018; 18(1): 2.
[] [PMID: 29310573]
Hsu LC, Hsu LS, Lee TH. Association of apolipoprotein A1 and A5 polymorphisms with stroke subtypes in Han Chinese people in Taiwan. Gene 2019; 684: 76-81.
[] [PMID: 30367981]
Shou W, Wang Y, Xie F, et al. A functional polymorphism affecting the APOA5 gene expression is causally associated with plasma triglyceride levels conferring coronary atherosclerosis risk in Han Chinese Population. Biochim Biophys Acta 2014; 1842(11): 2147-54.
[] [PMID: 25151233]
Guardiola M, Cofán M, de Castro-Oros I, et al. APOA5 variants predispose hyperlipidemic patients to atherogenic dyslipidemia and subclinical atherosclerosis. Atherosclerosis 2015; 240(1): 98-104.
[] [PMID: 25770687]
Laurila PP, Naukkarinen J, Kristiansson K, et al. Genetic association and interaction analysis of USF1 and APOA5 on lipid levels and atherosclerosis. Arterioscler Thromb Vasc Biol 2010; 30(2): 346-52.
[] [PMID: 19910639]
Ding Y, Zhu MA, Wang ZX, Zhu J, Feng JB, Li DS. Associations of polymorphisms in the apolipoprotein APOA1-C3-A5 gene cluster with acute coronary syndrome. J Biomed Biotechnol 2012; 2012: 509420.
[] [PMID: 22675253]
You Y, Wu YH, Zhang Y, et al. Effects of polymorphisms in APOA5 on the plasma levels of triglycerides and risk of coronary heart disease in Jilin, northeast China: A case-control study. BMJ Open 2018; 8(6): e020016.
[] [PMID: 29866721]
Takeuchi F, Isono M, Katsuya T, et al. Association of genetic variants influencing lipid levels with coronary artery disease in Japanese individuals. PLoS One 2012; 7(9): e46385.
[] [PMID: 23050023]
Sharma V, Witkowski A, Witkowska HE, et al. Hypertriglyceridemia associated with the c. 553G> T APOA5 SNP results from aberrant hetero-disulfide bond formation. Arterioscler Thromb Vasc Biol 2014; 34(10): 2254.
[] [PMID: 25127531]
Evans D, Bode A, von der Lippe G, Beil FU, Mann WA. Cerebrovascular atherosclerosis in type III hyperlipidemia is modulated by variation in the apolipoprotein A5 gene. Eur J Med Res 2011; 16(2): 79-84.
[] [PMID: 21463987]
Celap I, Nikolac Gabaj N, Demarin V, Basic Kes V, Simundic AM. Genetic and lifestyle predictors of ischemic stroke severity and outcome. Neurol Sci 2019; 40(12): 2565-72.
[] [PMID: 31327072]
Diakite B, Hamzi K, Hmimech W, Nadifi S. GMRAVC. Genetic polymorphisms of T-1131C APOA5 and ALOX5AP SG13S114 with the susceptibility of ischaemic stroke in Morocco. J Genet 2016; 95(2): 303-9.
[] [PMID: 27350673]
Szalai C, Keszei M, Duba J, et al. Polymorphism in the promoter region of the apolipoprotein A5 gene is associated with an increased susceptibility for coronary artery disease. Atherosclerosis 2004; 173(1): 109-14.
[] [PMID: 15177130]
Dallongeville J, Cottel D, Montaye M, Codron V, Amouyel P, Helbecque N. Impact of APOA5/A4/C3 genetic polymorphisms on lipid variables and cardiovascular disease risk in French men. Int J Cardiol 2006; 106(2): 152-6.
[] [PMID: 16321685]
Kao JT, Wen HC, Chien KL, Hsu HC, Lin SW. A novel genetic variant in the apolipoprotein A5 gene is associated with hypertriglyceridemia. Hum Mol Genet 2003; 12(19): 2533-9.
[] [PMID: 12915450]
Reyes-Soffer G, Sztalryd C, Horenstein RB, et al. Effects of APOC3 heterozygous deficiency on plasma lipid and lipoprotein metabolism. Arterioscler Thromb Vasc Biol 2019; 39(1): 63-72.
[] [PMID: 30580564]
Lin B, Huang Y, Zhang M, Wang J, Wu Y. Association between apolipoprotein C3 Sst I, T-455C, C-482T and C1100T polymorphisms and risk of coronary heart disease. BMJ Open 2014; 4(1): e004156.
[] [PMID: 24430880]
Russo GT, Meigs JB, Cupples LA, et al. Association of the Sst-I polymorphism at the APOC3 gene locus with variations in lipid levels, lipoprotein subclass profiles and coronary heart disease risk: the Framingham offspring study. Atherosclerosis 2001; 158(1): 173-81.
[] [PMID: 11500189]
Wulff AB, Nordestgaard BG, Tybjærg-Hansen A. APOC3 loss-offunction mutations, remnant cholesterol, low-density lipoprotein cholesterol, and cardiovascular risk: mediation-and meta-analyses of 137 895 individuals. Arterioscler Thromb Vasc Biol 2018; 38(3): 660-8.
[] [PMID: 29348120]
Pallaud C, Sass C, Zannad F, Siest G, Visvikis S. APOC3, CETP, fibrinogen, and MTHFR are genetic determinants of carotid intimamedia thickness in healthy men (the Stanislas cohort). Clin Genet 2001; 59(5): 316-24.
[] [PMID: 11359462]
Sun M, Chen L, Liu H, Ma L, Wang T, Liu Y. Association of the S2 allele of the SstI polymorphism in the apoC3 gene with plasma apoCIII interacts with unfavorable lipid profiles to contribute to atherosclerosis in the Li ethnic group in China. Lipids Health Dis 2017; 16(1): 220.
[] [PMID: 29162127]
Zhang JZ, Xie X, Ma YT, et al. Association between apolipoprotein C-III gene polymorphisms and coronary heart disease: a metaanalysis. Aging Dis 2016; 7(1): 36-44.
[] [PMID: 26816662]
Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis: An Official Journal of the American Heart Association. Inc 1988; 8(1): 1-21.
Huang L, Hua Z, Xiao H, et al. CRISPR/Cas9-mediated ApoE-/- and LDLR-/- double gene knockout in pigs elevates serum LDL-C and TC levels. Oncotarget 2017; 8(23): 37751-60.
[] [PMID: 28465483]
Fang B, Ren X, Wang Y, et al. Apolipoprotein E deficiency accelerates atherosclerosis development in miniature pigs. Dis Model Mech 2018; 11(10): dmm036632.
[] [PMID: 30305304]
Berkinbayev S, Rysuly M, Mussayev A, et al. Apolipoprotein gene polymorphisms (APOB, APOC111, APOE) in the development of coronary heart disease in ethnic groups of Kazakhstan. J Genet Syndr Gene Ther 2014; 5(2): 216.
[PMID: 24772377]
Granér M, Kahri J, Varpula M, et al. Apolipoprotein E polymorphism is associated with both carotid and coronary atherosclerosis in patients with coronary artery disease. Nutr Metab Cardiovasc Dis 2008; 18(4): 271-7.
[] [PMID: 17462871]
Doliner B, Dong C, Blanton SH, et al. Apolipoprotein E gene polymorphism and subclinical carotid atherosclerosis: The Northern Manhattan study. J Stroke Cerebrovasc Dis 2018; 27(3): 645-52.
[] [PMID: 29103864]
Dong C, Nevins JR, Goldschmidt-Clermont PJ. ABCA1 Single Nucleotide Polymorphisms: Snipping at the Pathogenesis of Atherosclerosis. Circ Res 2001; 88(9): 855-7.
Singaraja RR, Brunham LR, Visscher H, Kastelein JJ, Hayden MR. Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene. Arterioscler Thromb Vasc Biol 2003; 23(8): 1322-32.
[] [PMID: 12763760]
Fitzgerald ML, Mujawar Z, Tamehiro N. ABC transporters, atherosclerosis and inflammation. Atherosclerosis 2010; 211(2): 361-70.
[] [PMID: 20138281]
Lutucuta S, Ballantyne CM, Elghannam H, Gotto AM Jr, Marian AJ. Novel polymorphisms in promoter region of ATP binding cassette transporter gene and plasma lipids, severity, progression, and regression of coronary atherosclerosis and response to therapy. Circ Res 2001; 88(9): 969-73.
[] [PMID: 11349008]
Kyriakou T, Hodgkinson C, Pontefract DE, et al. Genotypic effect of the -565C>T polymorphism in the ABCA1 gene promoter on ABCA1 expression and severity of atherosclerosis. Arterioscler Thromb Vasc Biol 2005; 25(2): 418-23.
[] [PMID: 15528481]
Andrikovics H, Pongrácz E, Kalina E, et al. Decreased frequencies of ABCA1 polymorphisms R219K and V771M in Hungarian patients with cerebrovascular and cardiovascular diseases. Cerebrovasc Dis 2006; 21(4): 254-9.
[] [PMID: 16446539]
Ma XY, Liu JP, Song ZY. Associations of the ATP-binding cassette transporter A1 R219K polymorphism with HDL-C level and coronary artery disease risk: a meta-analysis. Atherosclerosis 2011; 215(2): 428-34.
[] [PMID: 21310416]
Xu Y, Li Z. Relationship between ABCA1 gene polymorphism and lacunar infarction combined with arteriosclerosis in patients. Exp Ther Med 2018; 16(2): 1323-7.
[] [PMID: 30112062]
Benton JL, Ding J, Tsai MY, et al. Associations between two common polymorphisms in the ABCA1 gene and subclinical atherosclerosis: Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 2007; 193(2): 352-60.
[] [PMID: 16879828]
Kolovou V, Marvaki A, Karakosta A, et al. Association of gender, ABCA1 gene polymorphisms and lipid profile in Greek young nurses. Lipids Health Dis 2012; 11(1): 62.
[] [PMID: 22668585]
Kolovou V, Marvaki A, Boutsikou M, et al. Effect of ATP-binding cassette transporter A1 (ABCA1) gene polymorphisms on plasma lipid variables and common demographic parameters in Greek nurses. Open Cardiovasc Med J 2016; 10: 233-9.
[] [PMID: 27990182]
Ergen A, Isbir S, Tekeli A, Isbir T. Investigation of ABCA1 C69T and G-191C polymorphisms in coronary artery disease in vivo 2008; 22(2): 187-90.
Cao XL, Yin RX, Wu DF, et al. Genetic variant of V825I in the ATP-binding cassette transporter A1 gene and serum lipid levels in the Guangxi Bai Ku Yao and Han populations. Lipids Health Dis 2011; 10(1): 14.
[] [PMID: 21247457]
Song J, Jiang X, Cao Y, Juan J, Wu T, Hu Y. Interaction between an ATP-Binding Cassette A1 (ABCA1) variant and egg consumption for the risk of ischemic stroke and carotid atherosclerosis: a family-based study in the Chinese population. J Atheroscler Thromb 2019; 26(9): 835-45.
[] [PMID: 30828007]
Jonas A. Lipoprotein structure Biochemistry of lipids, lipoproteins and membranes 4th ed. 2002; 483-504.
German JB, Smilowitz JT, Zivkovic AM. Lipoproteins: When size really matters. Curr Opin Colloid Interface Sci 2006; 11(2-3): 171-83.
[] [PMID: 20592953]
Ouatou S, Ajjemami M, Charoute H, et al. Association of APOA5 rs662799 and rs3135506 polymorphisms with arterial hypertension in Moroccan patients. Lipids Health Dis 2014; 13(1): 60.
[] [PMID: 24684850]
Al-Bustan SA, Alnaqeeb MA, Annice BG, Ebrahim GA, Refai TM. Genetic association of APOB polymorphisms with variation in serum lipid profile among the Kuwait population. Lipids Health Dis 2014; 13(1): 157.
[] [PMID: 25292352]
Liu C, Yang J, Han W, et al. Polymorphisms in ApoB gene are associated with risk of myocardial infarction and serum ApoB levels in a Chinese population. Int J Clin Exp Med 2015; 8(9): 16571-7.
[PMID: 26629186]
Gu QL, Han Y, Lan YM, et al. Association between polymorphisms in the APOB gene and hyperlipidemia in the Chinese Yugur population. Braz J Med Biol Res 2017; 50(11)e6613
[] [PMID: 28902930]

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Year: 2020
Published on: 12 October, 2020
Page: [4261 - 4271]
Pages: 11
DOI: 10.2174/1381612826666200614180958
Price: $65

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