Association of Kruppel-like factor 2 polymorphisms with the risk of coronary artery disease

Yıl 2023, Cilt: 48 Sayı: 2, 583 - 592, 02.07.2023

Ulaş Değirmenci , Metin Yıldırım , Merih Akkapulu , Ali Yalın , Dilek çiçek Dilek çiçek , Ragıp Onur Öztornacı , Bahar Taşdelen , Serap Yalın

https://doi.org/10.17826/cumj.1283236

Öz

Purpose: Coronary artery disease is defined as complications that develop in proportion to the prevalence of ischemia due to occlusion of the coronary arteries and the resulting cell death. The development of atherosclerosis is significantly influenced by endothelial cell dysfunction. Kruppel-like factor 2, a transcription factor, has been shown to regulate critical biological events in endothelial biology, such as vascular tone, migration, proliferation, vasoreactivity, and angiogenesis. In our study, it was aimed to clarify the relationship between coronary artery disease and Kruppel-like factor 2 protein levels and C1239A polymorphisms.
Materials and Methods: 191 individuals who underwent coronary angiography at Mersin University Faculty of Medicine, Department of Cardiology, Health, Research and Application Center were included in the study. Measurements of serum fasting blood glucose, HDL cholesterol, total cholesterol, and triglyceride levels were performed on the AU5800 (Beckman Coulter, United States) autoanalyzer. Serum LDL levels were calculated using the Friedwald equation. Serum Kruppel-like factor 2 protein levels were measured by sandwich enzyme-linked immunoassay method on the Multiskan GO (Thermo Scientific, Finland) device. Kruppel-like factor 2 C1239A variations were detected on the Applied Biosystem VIIA™ 7 Real-Time PCR (Life Technologies Co., United States) device by TaqMan® single nucleotide polymorphism (SNP) genotyping method.
Results: Men had a 3.8-fold higher risk of CAD than women. (Odd’s ratio 3.83, 95% Confidence interval 1.98-7.39; p<0.001). Kruppel-Like Factor 2 protein levels were not significantly different amongst the groups. Kruppel-like factor 2 C1239A polymorphisms were not associated with coronary artery disease.
Conclusion: More comprehensive studies with larger sample groups including other gene regions and meta-analysis studies are needed to determine the relationship between Kruppel-like factor 2 gene polymorphisms and coronary artery disease.

Anahtar Kelimeler

Coronary artery disease, Atheroseclerosis, Endothel, Kruppel-like factor 2, Single nucleotide polymorphism

Destekleyen Kurum

Mersin Üniversitesi Bilimsel Araştırma Projeleri Birimi

Proje Numarası

2018-2 TP3-2983

Teşekkür

This research was supported by the Research Foundation of Mersin University, Mersin, Turkey (Grant no. 2018-2 TP3-2983)

Kruppel benzeri faktör 2 polimorfizmlerinin koroner arter hastalığı riski ile ilişkisi

Öz

Amaç: Koroner arter hastalığ, koroner arterlerin tıkanmasıyla iskemi oluşması ve sonucunda gerçekleşen hücre ölümlerinin yaygınlığıyla orantılı gelişen komplikasyonlar olarak tanımlanır. Ateroskleroz oluşumunda endotel hücrelerinin disfonksiyonu önemli rol oynamaktadır. Bir transkripsiyon faktörü olan Kruppel benzeri faktör 2’nin endotel biyolojisinde vasküler tonus, migrasyon, proliferasyon, vazoreaktivite ve anjiyogenez gibi önemli biyolojik olayları düzenlediği ortaya konulmuştur. Çalışmamızda Kruppel benzeri faktör 2 protein düzeyleri ve C1239A polimorfizmlerinin koroner arter hastalığıyla ilişkisinin aydınlatılması amaçlandı.
Gereç ve Yöntem: Mersin Üniversitesi Tıp Fakültesi Hastanesi Kardiyoloji Polikliniğinde koroner anjiyografi yapılan 191 birey çalışmaya dahil edildi. Serum açlık kan şekeri, total kolesterol, HDL kolesterol ve trigliserit düzeylerinin ölçümleri AU5800 (Beckman Coulter, Amerika Birleşik Devletleri) otoanalizöründe yapıldı. Serum LDL düzeyleri Friedwald eşitliği kullanılarak hesaplandı. Serum Kruppel benzeri faktör 2 protein düzeyleri sandviç enzim bağlı immünoassay yöntemiyle Multiskan GO (Thermo Scientific, Finlandiya) cihazında çalışıldı. Kruppel benzeri faktör 2 C1239A varyasyonları TaqMan® tek nükleotid polimorfizm (SNP) genotiplendirme yöntemiyle Applied Biyosistem VIIA ™ 7 Real-Time PCR (Life Technologies Co., Amerika Birleşik Devletleri) cihazında saptandı.
Bulgular: Erkeklerin kadınlara göre KAH açısından 3,8 kat daha riskli olduğu saptandı (Odd’s Oranı 3,83, %95 Güven Aralığı 1,98-7,39; p<0,001). Kruppel Benzeri Faktör 2 protein düzeylerinin gruplar arasında anlamlı farklılık göstermediği saptandı. Kruppel benzeri faktör 2 C1239A polimorfizmlerinin koroner arter hastalığı için risk teşkil etmediği saptandı.
Sonuç: Kruppel benzeri faktör 2 gen polimorfizmlerinin KAH için risk faktörü olup olmadığının ortaya konulması için diğer gen bölgelerini de içeren daha geniş örneklem gruplarıyla yapılacak daha kapsamlı çalışmalara ve meta analiz çalımalarına ihtiyaç duyulduğu düşünülmektedir.

Anahtar Kelimeler

Koroner arter hastalığı, ateroskleroz, endotel, kruppel benzeri faktör 2, tek nükleotid polimorfizmi

Proje Numarası

2018-2 TP3-2983

Kaynakça

• Greenland P, Alpert JS, Beller GA, Benjamin EJ, Budoff MJ, Fayad ZA et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American college of cardiology foundation/American heart association task force on practice guidelines. J Am Coll Cardiol. 2010;56:50-103.
• Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJS et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The task force for the diagnosis and treatment of acute and chronic heart failure of the European society of cardiology (ESC). Developed with the special contribution of the heart failure association (HFA) of the ESC. Eur J Heart Fail. 2016;18:891-975.
• Robert E, Rozensweig G, Rozensweig A. Principles of Molecular Medicine. 1st ed. New Jersey, USA: Humana Press Tawata, 1998;133-40.
• Fuster V. Lewis A. Conner memorial lecture. Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation. 1995;91:256-64.
• Karabacak A, Özhan H. Atherosclerotic risk factors-I: Genetic, physiological and other features. Turkiye Klinikleri J Cardiol-Special Topics. 2011;4:19-24 (in Turkish with an abstract in English).
• Chen M, Masaki T, Sawamura T. LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis. Pharmacol Ther. 2002;95:89-100.
• Lusis AJ. Atherosclerosis. Nature. 2000;407:233-41.
• Atkins GB, Jain MK. Role of Krüppel-like transcription factors in endothelial biology. Circ Res. 2007;100:1686-95.
• Wani MA, Conkright MD, Jeffries S, Hughes MJ, Lingrel JB. cDNA isolation, genomic structure, regulation,and chromosomal localization of human lung Kruppel-like factor. Genomics. 1999;60:78-86.
• Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994;76:301-14.
• SenBanerjee S, Lin Z, Atkins GB, Greif DM, Rao RM, Kumar A et al. KLF2 is a novel transcriptional regulator of endothelial proinflammatory activation. J Exp Med. 2004;199:1305-15.
• Takada Y, Shinkai F, Kondo S, Yamamoto S, Tsuboi H, Korenaga R et al. Fluid shear stress increases the expression of thrombomodulin by cultured human endothelial cells. Biochem Biophys Res Commun. 1994;205:1345-52.
• Topper JN, Cai J, Falb D, Gimbrone MA Jr. Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc Natl Acad Sci U S A. 1996;93:10417-22.
• Bevilacqua MP, Schleef RR, Gimbrone MA Jr, Loskutoff DJ. Regulation of the fibrinolytic system of cultured human vascular endothelium by interleukin 1. J Clin Invest. 1986;78:587-91.
• Bombeli T, Karsan A, Tait JF, Harlan JM. Apoptotic vascular endothelial cells become procoagulant. Blood. 1997;89:2429-42.
• Conway EM, Rosenberg RD. Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells. Mol Cell Biol. 1988;8:5588-92.
• Lin Z, Kumar A, SenBanerjee S, Staniszewski K, Parmar K, Vaughan DE et al. Kruppel-like factor 2 (KLF2) regulates endothelial thrombotic function. Circ Res. 2005;96:48-57.
• Folkman J, Shing Y. Angiogenesis. J Biol Chem. 1992;267:10931-4.
• Jain RK. Molecular regulation of vessel maturation. Nat Med. 2003;9:68-93.
• Mukhopadhyay D, Zeng H, Bhattacharya R. Complexity in the vascular permeability factor/vascular endothelial growth factor (VPF/VEGF)-receptors signaling. Mol Cell Biochem. 2004;264:51-61.
• Bielenberg DR, Hida Y, Shimizu A, Kaipainen A, Kreuter M, Kim CC et al. Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J Clin Invest. 2004;114:1260–71.
• Dekker RJ, Boon RA, Rondaij MG, Kragt A, Volger OL, Elderkamp YW et al. KLF2 provokes a gene expression pattern that establishes functional quiescent differentiation of the endothelium. Blood. 2006;107:4354-63.
• Keys A, Taylor HL, Blackburn H, Brozek J, Anderson JT, Simonson E. Coronary heart disease among Minnesota business and professional men followed fifteen years. Circulation. 1963;28:381-95.
• Kannel WB. Blood pressure as a cardiovascular risk factor: prevention and treatment. JAMA. 1996;275:1571-76.
• Jousilahti P, Vartiainen E, Tuomilehto J. Sex, age, cardiovascular risk factors, and coronary heart disease: A prospective follow-up study of 14,786 middle -aged men and women in Finland. Circulation. 1999;99:1165.
• Grundy SM, Benjamin IJ, Burke GL, Chait A, Eckel RH, Howard BV et al. Diabetes and cardiovascular disease: A statement for healthcare professionals from the American Heart Association. Circulation. 1999;100:1134-40.
• Kannel WB. Blood pressure as a cardiovascular risk factor: prevention and treatment. JAMA. 1996;275:1571-76.
• Nordlie MA, Wold LE, Kloner RA. Genetic contributors toward increased risk for ischemic heart disease. J Mol Cell Cardiol. 2005;39:667-79.
• Meirhaege A, Cottel D, Amouyel P. A study of the relationships between KLF2 polymorphisms and body weight control in a French population. BMC Med Genet. 2006;7:26.
• Gutierrez-Aguilar R, Benmezroua Y, Vaillant E, Balkau B, Marre M, Charpentier G et al. Analysis of KLF transcription factor family gene variants in type 2 diabetes. BMC Med Genet. 2007;8:53.
• Eichstaedt CA, Song J, Viales RR, Pan Z, Benjamin N, Fischer C et al. First identification of Krüppel-like factor 2 mutation in heritable pulmonary arterial hypertension. Clin Sci (Lond). 2017;131:689-98.