Meral Kucuk, Aysegul Bayramoglu, Semire Gocmen, Yunus Kucukkaya, Okay Abaci, Halil Guler, Abdullah Arpaci, Mustafa Korkmaz

Koroner Arter Hastalığında MTHFR ve MMP-9 Genetik Variantları

Amaç: Koroner arter hastalığı (KAH), hem genetik hem de çevresel faktörlerden etkilenen çok faktörlü bir hastalıktır. Aday genlerdeki tek nükleotid polimorfizmleri (SNP) bu tür multifaktöryel hastalıklara yatkınlığa neden olurlar. Bu yüzden, KAH etiyopatogenezinde rol oynayan genlerde SNPlerin araştırılması, önemli hale gelir. Bu çalışmada, KAH oluşumu üzerinde, matriks metalloproteinaz-9 (MMP9) -1562 C/T ve metilentetrahidrofolat redüktaz (MTHFR) 677 C/T polimorfizmlerinin bağımsız ve sinerjistik etkileri araştırıldı.Yöntemler: 109 koroner arter hastası ve 108 sağlıklı kontrol olmak üzere toplam 217 birey incelendi. MTHFR 677 C/T ve MMP-9 -1562 C/T polimorfizmleri için genotipler polimeraz zincir reaksiyonu (PCR)- restriksiyon fragmanı uzunluk polimorfizmi (RFLP) ile belirlendi.Bulgular: KAH ile MMP-9 -1562 C/T ve MTHFR - 677 C/T polimorfizmlerinin genotipleri ve alel frekansları arasında istatistiksel olarak anlamlı bir farklılık olmadığı bulundu. (p> 0.05) MMP9 -1562 C/T polimorfizmi için TT homozigot genotipi hiç bir grupta bulunmadı. Bununla birlikte, Güneydoğu Anadolu Bölgesinde C aleli ve CC genotipi her iki polimorfizm için hakim iken, TT genotipi ise çok nadir olarak bulundu. Sonuç: MTHFR 677 C/T ve MMP9 -1562 C/T polimorfizmleri ile koroner arter hastalığı arasında ilişki bulunmadı. Ancak Güneydoğu Anadolu bölgesinde TT genotipinin çok nadir olduğu belirlendi

Anahtar Kelimeler:

Metilentetrahidrofolat redüktaz MTHFR 677 C/T, matriks metalloproteinaz-9 (MMP9) -1562 C/T, polimorfizm, koroner arter hastalığı

MTHFR and MMP-9 Genetic Variants in Coronary Artery Disease

Objective: Coronary artery disease (CAD) is a multifactorial disease that influenced by both genetic and environmental factors. Single nucleotide polymorphisms (SNPs) in the candidate genes produce susceptibility to such multifactorial diseases. Therefore, investigations of SNPs, in the genes that may play role in etiopathogenesis of CAD, become crucial. In the present study we investigated the both independent and synergistically effects of matrix metalloproteinase (MMP) -1562 C/T and methylenetetrahydrofolate reductase (MTHFR) 677 C/T polymorphisms on the CAD occurrence.Methods: In total 217 individuals, 109 coronary artery disease patients and 108 healthy controls were examined. We determined the genotypes for MMP-9 -1562 C/T and MTHFR 677 C/T polymorphisms by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP).Results: We found no statistically significant differences between genotypes and allelic frequencies of both MMP-9 -1562 C/T and MTHFR 677 C/T polymorphisms and CAD (p>0.05). No TT homozygous genotype was found in any of groups for MMP9 -1562 C/T polymorphism. However, while C allele and CC genotype was found to be highly, TT genotype was found to be very rare for both polymorphisms in Southeastern Anatolia.Conclusion: We have found no associations between MMP9 -1562 C/T and MTHFR 677 C/T polymorphisms and coronary artery disease. However, TT genotype was determined to be very rare in Southeast Anatolia.Key words: Methylenetetrahydrofolate reductase (MTHFR) -677, Matrix metalloproteinase 9 (MMP9) -1562, polymorphism, coronary artery disease

Keywords:

-,

PDF

___

Morgan AR, Zhang B, Tapper W, et al. Haplotypic analysis of the MMP-9 gene in relation to coronary artery disease. J Mol Med 2003;81:321-326.
Danzig V, Míková B, Kuchynk P, et al. Levels of Circulating Biomarkers at Rest and after Exercise in Coronary Artery Disease Patients Physiol Res 2010;59:385-392.
Lusis AJ. Atherosclerosis. Nature 2000;407:233-241.
Zhi H., Wang H, Ren L, et al. Functional polymorphisms of matrix metallopeptidase-9 and risk of coronary artery disease in a Chinese population. Mol Biol Rep 2010;37:13-20.
Bayramoglu A, Urhan-Kucuk M, Guler HI, et al. Is there any genetic predisposition of MMP-9 gene C1562T and MTHFR gene C677T polymorphisms with essential hypertension? Cytotechnology 2015;67:115-22.
Tayebjee MH, Lip GY, Tan KT, et al. Plasma matrix etalloproteinase-9, tissue inhibitor of metalloproteinase-2, and
CD40 ligand levels in patients with stable coronary artery disease. Am J Cardiol 2005;96:339-345.
Nannı S, Melandrı G, Hanemaaıjer R, et al. Matrix etalloproteinases
in premature coronary atherosclerosis: influence of inhibitors, inflammation, and genetic polymorphisms. Transl Res 2007;149:137-144.
Kai H, Ikeda H, Yasukawa H, et al. Peripheral blood levels of matrix metalloproteases-2 and -9 are elevated in patients with acute coronary syndromes. J Am Coll Cardiol 1998;32:368-372.
Opstad TB, Pettersen AA, Weiss TW, et al. Genetic variation, gene-expression and circulating levels of matrix etalloproteinase-9 in patients with stable coronary artery disease. Clin Chim Acta 2012;413:113-120.
Zhang B, Ye S, Herrmann SM, et al. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation 1999;99:1788-1794.
Abilleira S, Bevan S., Markus HS. The role of genetic variants of matrix metalloproteinases in coronary and carotid atherosclerosis. J Med Genet 2006;43:897-901.
Saedi M, Vaisi-Raygani A, Khaghani S, et al. Matrix metalloproteinase-9 functional promoter polymorphism 1562C>T increased risk of early-onset coronary artery disease. Mol Biol Rep 2012;39:555-562.
İzmirli M, Aldemir Ö, Gögebakan B, et al. The studies about
diseases concerning with contemplated MTHFR 677 C>T polymorphism. Dicle Medical Journal 2014;41:244-256.
Dikmen M. Molecular Biology of Methylenetetrahydrofolate Reductase (MTHFR) Enzyme and Its Association with Diseases. The Medical Journal of Kocatepe 2004;5:9-16.
Tripathi R, Tewari S, Singh PK, et al. Association of homocysteine
and methylenetetrahydrofolate reductase (MTHFR C677T) gene polymorphism with coronary artery disease (CAD) in the population of North India. Gen Mol Biology 2010;33:224-228.
Kanth VV, Golla JP, Sastry BK, et al. Genetic interactions between MTHFR (C677T), methionine synthase (A2756G, C2758G) variants with vitamin B12 and folic acid determine susceptibility to premature coronary artery disease in Indian population. J Cardiovasc Dis Res 2011;2:156-63.
Uğuz N, Erden G, Güngör O, et al. Determination of the frequency of MTHFR C677T and MTHFR A1298C polymorphisms
in persons with polymorphic MTHFR gene. J Clin Exp Invest 2012;3:472-476.
Teng Z, Wang L, Cai S, et al. The 677C/T (rs1801133) Polymorphism in the MTHFR gene contributes to colorectal
cancer risk: a meta-analysis based on 71 research studies. Plos One 2013;8:1-10.
Ghazouani L, Abboud N, Mtiraoui N, et al. Homocysteine and methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in Tunisian patients with severe coronary artery disease. J Thromb Thrombolysis 2009;27:191-197.
Vinukonda G, Mohammad NS, Nurul Jain J et al. Genetic and environmental influences on total plasma homocysteine and coronary artery disease (CAD) risk among South Indians. Clinica Chimica Acta. 2009;405:127-131.
Clarke R, Bennett DA, Parish S, et al. Homocysteine and Coronary Heart Disease: Metaanalysis of MTHFR Case-Control Studies, Avoiding Publication Bias. PLoS Med 2012;9:1-12.
Cho HJ, Chae IH, Park KW, et al. Functional polymorphism in the promoter region of the gelatinase B gene in relation to coronary artery disease and restenosis after percutaneous coronary intervention. J Hum Genet 2002;47:88-91.
Pöllänen PJ, Lehtimäki T, Mikkelsson J, et al. Matrix metalloproteinase 3 and 9 gene promoter polymorphisms: joint
action of two loci as a risk factor for coronary artery complicated
plaques. Atherosclerosis 2005;180:73-78.
Alp E, Menevse S, Tulmac M, et al. Lack of association between matrix metalloproteinase-9 and endothelial nitric oxide synthase gene polymorphisms and coronary artery disease in Turkish population. DNA Cell Biol 2009;28:343-350.
Li M, Shi J, Fu L, et al. Genetic polymorphism of MMP family and coronary disease susceptibility: A meta-analysis. Gene 2012;495:36-41.
Nuzzo D, Vasto S, Balistreri CR, et al. Role of proinflammatory
alleles in longevity and atherosclerosis: results of studies performed on -1562C/T MMP-9 in centenarians and myocardial infarction patients from Sicily. Ann NY Acad Sci 2006;1089:496-501.
Wang L, Ma YT, Xie X, et al. Interaction between MMP-9 gene polymorphisms and smoking in relation to myocardial infarction in a Uighur population. Clin Appl Thromb Hemost 2012;18:72-78.
Ibrahim S, Dessokiy OE. Prevalence of methylenetetrahydrofolate
gene (MTHFR) C677T polymorphism among chronic hemodialysis patients and its association with cardiovascular disease: a cross-sectional analysis. Clin Exp Nephrol 2009;13:501-507.
Rahimi Z, Nomani H, Mozafari H, et al. Factor V G1691A, prothrombin G20210A and methylenetetrahydrofolate reductase
polymorphism C677T are not associated with coronary artery disease and type 2 diabetes mellitus in western Iran. Blood Coagulation and Fibrinolysis 2009;20:252-256.
Guerzoni AR, Biselli PM, de Godoy MF, et al. Homocysteine and MTHFR and VEGF Gene Polymorphisms:Impact on Coronary Artery Disease. Arq Bras Cardiol 2009;92:249-254.
Pandey U, Kumari R, Nath B, et al. Association of angiotensin-
converting enzyme, methylene tetrahydrofolate reductase and paraoxonase gene polymorphism and coronary artery disease in an Indian population. Cardiology J 2011;18:385-394.
Gupta SK, Kotwal J, Kotwal A, et al. Role of homocysteine
& MTHFR C677T gene polymorphism as risk factors for coronary artery disease in young Indians. Indian J Med Res. 2012;135:506-512.
Li YY. Methylenetetrahydrofolate reductase C677T gene
polymorphism and coronary artery disease in a Chinese Han population: a meta-analysis. Metabolism 2012;61:846-852.
Wu N, Lu X, Hua Y, et al. Haplotype analysis of the Stromelysin-
(MMP3) and Gelatinase B (MMP9) genes in relation to coronary heart disease. Ann Hum Gen 2009;73:404-410.