The 3'UTR 188 C>T Polymorphism of the OLR1 Gene: Effects in Serum Oxidized LDL Levels and Metabolic Parameters in Patients with Coronary Artery Disease

Öz

Aim: Oxidized LDL, which stimulates signaling pathways that activate inflammatory reactions in endothelial cells during atherosclerosis, is defined as an important pathogenic factor in the development of cardiovascular diseases. The oxidized LDL receptor (LOX-1), which is the main receptor for oxidized LDL in endothelial cells, has the ability to specifically bind, internalize and degrade oxidized LDLs in endothelial cells. In this study, it was aimed to investigate the effect of 3'UTR188C>T polymorphism in the OLR1 gene encoding LOX-1 on serum oxidized LDL and lipid levels in the study groups consisting of coronary artery disease (CAD) patients and healthy controls, and to determine its relationship with lipid parameters in patients with CAD. Methods: Polymerase Chain Reaction and Restriction Fragment Length Polymorphism methods were used to detect the OLR1 gene 3'UTR188C>T polymorphism in groups of 50 CAD patients and 34 healthy controls. Statistical analyzes were performed with SPSS 20.0. Results: In the CAD group, oxidized LDL (p<0.001), total-cholesterol (p=0.020), Body Mass Indeks (BMI) (p=0.015), systolic (p<0.001) and diastolic (p=0.002) blood pressure levels and smoking frequency p=0.002) were higher, and serum HDL-C levels (p<0.001) were lower compared to healthy controls. OLR1 3'UTR188C>T genotype and allele distributions were found to be similar between the groups (p>0.05). The 188T allele was associated with higher oxidized LDL levels in both CAD (p<0.001) and control (p=0.013) groups. Patients with the 188TT genotype had high oxidized LDL (p<0.001), total cholesterol, LDL-cholesterol, triglyceride, and VLDL-cholesterol levels. Similarly, in healthy controls, the 188TT genotype was associated with high oxidized LDL, total- and LDL-cholesterol, triglyceride, VLDL-cholesterol, systolic blood pressure, and low serum HDL-cholesterol. Conclusion: Our findings indicate that the OLR1 3'UTR188C>T polymorphism may be associated with the development of CAD with its effects in favor of both serum oxidized LDL, which is a proatherogenic molecule, and an atherogenic lipid profile.

Anahtar Kelimeler

• Oxidized LDL
• LOX-1
• OLR1
• gene
• lipid
• coronary artery disease

OLR1 Geni 3’UTR 188 C>T Polimorfizmi: Koroner Arter Hastalarında Serum Okside LDL Düzeylerine ve Metabolik Parametrelere Etkileri

Öz

Amaç: Ateroskleroz sürecinde endotelyal hücrelerde enflamatuvar tepkimeleri aktive eden sinyal yolaklarını uyaran okside LDL, kardiyovasküler hastalıkların gelişiminde önemli bir patojenik faktör olarak tanımlanmaktadır. Endotel hücrelerinde okside LDL için başlıca reseptör olan okside LDL reseptörü (LOX-1), okside LDL’leri endotel hücrelerinde özgül olarak bağlayabilme, hücre içine alabilme ve degrade edebilme özelliğine sahiptir. Bu çalışmada LOX-1’i kodlayan OLR1 geninde 3’UTR188C>T polimorfizminin koroner arter hastaları ve sağlıklı kontrollerden oluşan çalışma gruplarında serum okside LDL ve lipid düzeylerine etkisinin araştırılarak KAH hastalarında lipid parametrelerle ilişkisinin belirlenmesi amaçlanmıştır. Yöntem: Çalışmaya katılan 50 KAH hastası ve 34 sağlıklı kontrolden oluşan gruplarda OLR1 geni 3’UTR188C>T polimorfizminin tespiti için Polimeraz Zincir Reaksiyonu ve Restriksiyon Fragman Uzunluk Polimorfizmi yöntemleri kullanılmıştır. İstatistiksel analiz SPSS 20.0 ile yapılmıştır. Bulgular: KAH grubunda okside LDL (p<0,001), total-kolesterol (p=0,020), Beden Kütle İndeksi (BKİ) (p=0,015), sistolik (p<0,001) ve diastolik (p=0,002) kan basıncı değerleri ve sigara kullanım sıklığı (p=0,002) sağlıklı kontrollere kıyasla yüksek ve serum HDL-K düzeyi düşük gözlenmiştir (p<0,001). OLR1 3’UTR188C>T genotip ve allel dağılımları gruplar arasında benzer bulunmuştur (p>0,05). 188T alleli hem KAH (p<0,001) hem de kontrol (p=0,013) gruplarında yüksek okside LDL düzeyleri ile ilişkili gözlenmiştir. 188TT genotipi taşıyan hastalarda okside LDL (p<0,001), total-kolesterol, LDL-kolesterol, trigliserid ve VLDL-kolesterol düzeyleri yüksekti. Benzer şekilde sağlıklı kontrollerde de 188TT genotipi yüksek okside LDL, total ve LDL-kolesterol, trigliserid, VLDL-kolesterol, sistolik kan basıncı ve düşük serum HDL-kolesterol düzeyi ile ilişkiliydi. Sonuç: Bulgular OLR1 3’UTR 188 C>T polimorfizminin hem proaterojenik bir molekül olan serum okside LDL hem de aterojenik lipid profili lehine etkileriyle KAH gelişimiyle ilişkili olabileceğine işaret etmektedir.

Anahtar Kelimeler

• Okside LDL
• LOX-1
• OLR1
• gen
• lipid
• koroner arter hastalığı

Destekleyen Kurum

Yazarlar finansal destek almadıklarını beyan ederler.

Teşekkür

Makale yazarları İstanbul Üniversitesi Sağlık Bilimleri Enstitüsü’ne destekleri için teşekkür eder.

Kaynakça

1. Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med. 1999;340:115-126.
2. Chen Q, Reis SE, Kammerer C, et al. Genetic variation in lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) gene and the risk of coronary artery disease. Circulation. 2003;107(25):3146-3151.
3. Kurban S, Mehmetoğlu İ. Okside düşük dansiteli lipoprotein otoantikorları ve klinik önemi. Türkiye Klinikleri J Med Sci. 2005;25:73-84.
4. Parthasarathy S, Raghavamenon A, Garelnabi MO, Santanam N. Oxidized low-density lipoprotein. Methods Mol Biol. 2010;610:403-417.
5. Sawamura T, Kume N, Aoyama T, et al. An endothelial receptor for oxidized low-density lipoprotein. Nature. 1997;386:73-77.
6. Valente AJ, Irimpen AM, Siebenlist U, Chandrasekar B. OxLDL induces endothelial dysfunction and death via TRAF3IP2: Inhibition by HDL3 and AMPK activators. Free Radic Biol Med. 2014;70:117-28.
7. Kataoka H, Kume N, Miyamoto S, et al. Oxidized LDL modulates Bax/Bcl-2 through the lectin like Ox-LDL receptor-1 in vascular smooth muscle cells. Arter Thromb Vasc Biol. 2001;21:955-960.
8. Vohra RS, Murphy JE, Walker JH, Ponnambalam S, Homer-Vanniasinkam S. Atherosclerosis and the lectin-like oxidized low-density lipoprotein scavenger receptor. Trends Cardiovasc Med. 2006;16(2):60-4.

9. Goyal T, Mitra S, Khaidakov M, et al. Current concepts of the role of oxidized LDL receptors in atherosclerosis. Curr Atheroscler Rep. 2012;14:150-159.
10. Aoyama T, Sawamura T, Furutani Y, et al. Structure and chromosomal assignment of the human lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1) gene. Biochem J. 1999;339(Pt1):177-184.
11. Feng Y, Cai Z, Tang Y, et al. TLR4/NF-KB signaling pathway-mediated and oxLDL-induced up-regulation of LOX-1, MCP-1, and VCAM-1 expressions in human umbilical vein endothelial cells. Genet Mol Res. 2014;13:680-695.
12. Xu S, Ogura S, Chen J, Little PJ, Moss J, Liu P. LOX-1 in atherosclerosis: Biological functions and pharmacological modifiers. Cell Mol Life Sci. 2013;70:2859-2872.
13. 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(1):89-100.
14. Mehta JL, Chen J, Hermonat PL, Romeo F, Novelli G. Lectin-like oxidized low-density lipoprotein receptor-1(LOX-1): A critical player in the development of atherosclerosis and related disorders. Cardiovasc Res. 2006;69(1):36-45.
15. Adachi H, Tsujimoto M. Endothelial scavenger receptors. Prog Lipid Res. 2006;45(5):379-404.
16. Xiu-ping C, Guan-hua DU. Lectin-like oxidized low-density lipoprotein receptor-1: Protein, ligands, expression and pathophysiological significance. Chin Med J. 2007;120(5):421-426.
17. Chen M, Nagase M, Fujita T, Narumiya S, Masaki T, Sawamura T. Diabetes enhances lectin-like oxidized LDL receptor-1 (LOX-1) expression in the vascular endothelium: Possible role of LOX-1 ligand and AGE. Biochem Biophys Res Commun. 2001;287:962-968.
18. Nagase M, Hirose S, Sawamura T, Masaki T, Fujita T. Enhanced expression of endothelial oxidized low-density lipoprotein receptor (LOX-1) in hypertensive rats. Biochem Biophys Res Commun. 1997;237(3):496-498.
19. Chen M, Kakutani M, Minami M, et al. Increased expression of lectin-like oxidized low density lipoprotein receptor-1 in initial atherosclerotic lesions of watanabe heritable hyperlipidemic rabbits. Arter Thromb Vasc Biol. 2000;20(4):1107-1115.
20. Pirillo A, Norata GD, Catapano AL. LOX-1, OxLDL, and atherosclerosis. Mediatotrs Inflamm. 2013;2013:152786.
21. Chen M, Narumiya S, Masaki T, Sawamura T. Conserved C-terminal residues within the lectin-like domain of LOX-1 are essential for oxidized low-density-lipoprotein binding. Biochem J. 2001;355(Pt2):289-296.
22. Trabetti E, Biscuola M, Cavallari U, et al. On the association of the oxidized LDL reeptor 1 (OLR1) gene in patients with acute myocardial infarction or coronary artery disease. Eur J Hum Genet. 2006;14(1):127-130.
23. Mango R, Clementi F, Borgiani P, et al. Association of single nucleotide polymorphisms in the oxidised LDL receptor 1 (OLR1) gene in patients with acute myocardial infarction. J Med Genet. 2003;40(12):933-936.
24. Ohmori R, Momiyama Y, Nagano M, et al. An oxidized low density lipoprotein receptor gene variant is inversely associated with the severity of coronary artery disease. Clin Cardiol. 2004;27(11):641-644.
25. Tatsuguchi M, Furutani M, Hinagata JI, et al. Oxidized LDL receptor gene (OLR1) is associated with the risk of myocardial infarction. Biochem Biophys Res Commun. 2003;303(1):247-250.
26. Wang L, Yanuck D, Beecham A, et al. A candidate gene study revealed sex-specific association between the OLR1 gene and carotid plaque. Stroke. 2011;42(3):588-592.
27. Novelli G, Borgiani P, Mango R, Lauro R, Romeo F. Further evidence that polymorphisms of the OLR1 gene are associated with susceptibility to coronary artery disease and myocardial infarction. Nutr Metab Cardiovasc Dis. 2007;17(3):e7-8.
28. Puccetti L, Pasqui AL, Pastorelli M, et al. 3'UTR/T polymorphism of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is associated with modified anti-platelet activity of atorvastatin in hypercholesterolemic subjects. Atherosclerosis. 2005;183(2):322-328.
29. Kurnaz O, Aydogan HY, Isbir CS, Tekeli A, Isbir T. Is LOX-1 K167N polymorphism protective for coronary artery disease? In Vivo. 2009;23(6):969-73.
30. Kurnaz O, Akadam-Teker AB, Yilmaz-Aydoğan H, Tekeli A, Isbir T. The LOX-1 3'UTR188CT polymorphism and coronary artery disease in Turkish patients. Mol Biol Rep. 2012;39(4):4351-8.
31. Kurnaz-Gomleksiz O, Kucukhuseyin O, Ozkok E, Bugra Z, Ozturk O, Yilmaz-Aydogan H. Are IVS4 SNPs of OLR1 gene associated with coronary artery disease: Is there a linkage between IVS4 SNPs? Adv Clin Exp Med. 2018;27(3):321-326.
32. Score working group E. S. C. Cardiovascular risk collaboration. SCORE2 risk prediction algorithms: New models to estimate 10-year risk of cardiovascular disease in Europe. Eur Heart J. 2021;42(25):2439-54.
33. Gao S, Liu J. Association between circulating oxidized low-density lipoprotein and atherosclerotic cardiovascular disease. Chronic Dis Transl Med. 2017;3(2):89-94.
34. Ashraf MZ, Sahu A.Scavenger receptors: A key player in cardiovascular diseases. Biomol Concepts. 2012;3(4):371-380.
35. Cominacini L, Pasini AF, Garbin U, Davoli A, Tosetti ML, Sawamura T. Oxidized low density lipoprotein (ox-LDL) binding to ox-LDL receptor-1 in endothelial cells induces the activation of NF-kappaB through an increased production of intracellular reactive oxygen species. J Biol Chem. 2000;275(17):12633-12638.
36. Akhmedov A, Rozenberg I, Paneni F, et al. Endothelial overexpression of LOX-1 increases plaque formation and promotes atherosclerosis in vivo. Eur Heart J. 2014;35(40):2839-2848.
37. Shittu LA, Bankole MA, Ogundipe OA, et al. Weight reduction with improvement of serum lipid profile and ratios of sesamum radiatum leaves diet in a non-obese Sprague Dawley rats. African J Biotechnol. 2007;6(21):2428-2433.
38. Arslan C, Bayoglu B, Tel C, Cengiz M, Dirican A, Besirli K. Upregulation of OLR1 and IL17A genes and their association with blood glucose and lipid levels in femoropopliteal artery disease. Exp Ther Med. 2017;13(3):1160-1168.
39. Luedecking-Zimmer E, DeKosky ST, Chen Q, Barmada MM, Kamboh MI. Investigation of oxidized LDL-receptor 1 (OLR1) as the candidate gene for Alzheimer's disease on chromosome 12. Hum Genet. 2002;111(4-5):443-451.
40. Guo X, Xiang Y, Yang H, Yu L, Peng X, Guo R. Association of the LOX-1 rs1050283 polymorphism with risk for atherosclerotic cerebral infarction and its effect on sLOX-1 and LOX-1 expression in a Chinese population. J Atheroscler Thromb. 2017;24(6):572-582.
41. Sciacqua A, Presta I, Perticone M, et al. 3'-UTR OLR1/LOX-1 gene polymorphism and endothelial dysfunction: Molecular and vascular data in never-treated hypertensive patients. Intern Emerg Med. 2014;9(3):273-281.
42. Sentinelli F, Filippi E, Fallarino M, et al. The 3'-UTR C>T polymorphism of the oxidized LDL-receptor 1 (OLR1) gene does not associate with coronary artery disease in Italian CAD patients or with the severity of coronary disease. Nutr Metab Cardiovasc Dis. 2006;16(5):345-352.
43. Tripathi R, Tewari S, Ramesh V, Agarwal S. Oxidized LDL receptor 1 (OLR1) SNPs and CAD: A case-control association study in a North Indian population. J Biol Res-Thessalon. 2012;18:328-331.
44. Feng TY, Shan HW, Lang R. Associations between Lectin-like, oxidized low-density lipoprotein receptor-1 G501C and 3'-UTR-C188T polymorphisms with coronary artery disease: A meta-analysis. Int J Clin Exp Med. 2015;8(6):9275-9282.
45. Hu B, Li D, Sawamura T, Mehta JL. Oxidized LDL through LOX-1 modulates LDL-receptor expression in human coronary artery endothelial cells. Biochem Biophys Res Commun. 2003;307(4):1008-12.
46. Yamanaka S, Zhang XY, Miura K, Kim S, Iwao H. The human gene encoding the lectin-type oxidized LDL receptor (OLR1) is a novel member of the natural killer gene complex with a unique expression profile. Genomics. 1998;54:191-199.
47. Kattoor AJ, Goel A, Mehta JL. LOX-1: Regulation, signaling and its role in atherosclerosis. Antioxidants. 2019;8(7):218.
48. Li D, Williams V, Liu L, et al. Expression of lectin-like oxidized low-density lipoprotein receptors during ischemia-reperfusion and its role in determination of apoptosis and left ventricular dysfunction. J Am Coll Cardiol. 2003;41(6):1048-1055.