Tammam SİPAHİ, Babürhan GÜLDİKEN, Sibel GÜLDİKEN, Sedat ÜSTÜNDAĞ, Nilda TURGUT, Metin BUDAK, Suat CAKİNA, Hülya ÖZKAN, Seralp ŞENER

Anjiyotensin Dönüştürücü Enzim ve Anjiyotensin II Tip 1 Reseptörü Gen Polimorfizmlerinin Trakya Bölgesindeki Türk Hastalarda Görülen İskemik İnme ile İlişkisi

Amaç: Bu çalışmanın amacı, Trakya bölgesinde yaşayan iskemik inme geçirmiş hastalarda ACE insersiyon/delesyon (I/D) ve AT1R (A1166C) gen polimorfizmlerinin sıklığını, vasküler risk faktörleri ve inme alt-grupları ile ilişkisini araş- tırmaktır. Hastalar ve Yöntemler: Çalışmaya 162 iskemik inme geçirmiş hasta ile 146 sağlıklı olgu alındı. İskemik inme hastaları, ORG 10172 Akut İnme Tedavisi (TOAST) kriterlerine göre büyük ve küçük damar hastalığı olarak inme alt gruplarına ayrıldı. ACE I/D polimorfizmi polimeraz zincir reaksiyonu (PZR), AT1R (A1166C) gen polimorfizmi ise PZR ve restriksiyon fragment uzunluk polimorfizmi (RFLP) yöntemleri kullanılarak yapıldı. Bulgular: Hasta grubundaki ACE I/D genotip dağılımı (DD=34.0%, ID=50.0%, II=16.0%), kontrol grubu ile karşı- laştırıldığında (DD=34.3%, ID=49.7%, II=16.1%) fark bulunmadı. Ayrıca hasta grubundaki AT1R (A1166C) genotip dağılımları ile (AA=58.0%, CA=34.6% ve CC=7.4%) kontrol grubu ile karşılaştırıldığında (AA=60.1%, CA=35.7% ve CC=4.2%) anlamlı fark saptanmadı. Her iki inme alt grubu arasında ACE I/D ve AT1R (A1166C) polimorfizmlerinin dağılımı açısından farklılık bulunmadı. Sonuç: Çalışmamızda Trakya bölgesinde yaşayan insanlarda ACE I/D ve AT1R (A1166C) gen polimorfizmlerinin iskemik inme gelişmesinde genetik risk faktörleri olmadıkları belirlendi.

Anahtar Kelimeler:

İskemik inme, ACE I/D gen polimorfizmi, AT1R (A1166C) gen polimorfizmi, renin-anjiyotensin sistemi.

The Association of Gene Polymorphisms of the Angiotensin- Converting Enzyme and Angiotensin II Receptor Type 1 with Ischemic Stroke in Turkish Subjects of Trakya Region

Objectives: The aim of this study was to investigate the frequency of ACE insertion/deletion (I/D) and AT1R (A1166C) gene polymorphisms in ischemic stroke patients in Trakya region and the relation between these gene polymorphisms and stroke subtypes and vascular risk factors. Patients and Methods: The study involved 162 patients with ischemic stroke and 146 control subjects. Ischemic stroke patients were divided into large and small vessel disease subgroups according to ORG 10172 in Acute Stroke Treatment TOAST criteria. The ACE I/D polymorphism was investigated using polymerase chain reaction (PCR), and the AT1R (A1166C) polymorphism was identified using PCR and restriction fragment length polymorphism (RFLP) assay. Results: The ACE I/D genotype distribution in patients (DD=34.0%, ID=50.0%, II=16.0%) did not differ from those in controls (DD=34.3%, ID=49.7%, II=16.1%). The AT1R A1166C genotype distribution in patients (AA=58.0%, CA=34.6%, CC=7.4%) did not significantly differ from those in controls (AA=60.1%, CA=35.7%, CC=4.2%). There was also no difference among the stroke subgroups regarding the distribution of ACE I/D and AT1R (A1166C) polymorphisms. Conclusion: Our results show that ACE I/D and AT1R (A1166C) gene polymorphisms were not genetic risk factors for ischemic stroke in subjects in Trakya region. Turkish Başlık: Anjiyotensin Dönüştürücü Enzim ve Anjiyotensin II Tip 1 Reseptörü Gen Polimorfizmlerinin Trakya Bölgesindeki Türk Hastalarda Görülen İskemik İnme ile İlişkisi Anahtar Kelimeler: İskemik inme; ACE I/D gen polimorfizmi; AT1R (A1166C) gen polimorfizmi; renin-anjiyotensin sistemi Amaç: Bu çalışmanın amacı, Trakya bölgesinde yaşayan iskemik inme geçirmiş hastalarda ACE insersiyon/delesyon (I/D) ve AT1R (A1166C) gen polimorfizmlerinin sıklığını, vasküler risk faktörleri ve inme alt-grupları ile ilişkisini araştırmaktır. Hastalar ve Yöntemler: Çalışmaya 162 iskemik inme geçirmiş hasta ile 146 sağlıklı olgu alındı. İskemik inme hastaları, ORG 10172 Akut İnme Tedavisi (TOAST) kriterlerine göre büyük ve küçük damar hastalığı olarak inme alt gruplarına ayrıldı. ACE I/D polimorfizmi polimeraz zincir reaksiyonu (PZR), AT1R (A1166C) gen polimorfizmi ise PZR ve restriksiyon fragment uzunluk polimorfizmi (RFLP) yöntemleri kullanılarak yapıldı. Bulgular: Hasta grubundaki ACE I/D genotip dağılımı (DD=34.0%, ID=50.0%, II=16.0%), kontrol grubu ile karşılaştırıldığında (DD=34.3%, ID=49.7%, II=16.1%) fark bulunmadı. Ayrıca hasta grubundaki AT1R (A1166C) genotip dağılımları ile (AA=58.0%, CA=34.6% ve CC=7.4%) kontrol grubu ile karşılaştırıldığında (AA=60.1%, CA=35.7% ve CC=4.2%) anlamlı fark saptanmadı. Her iki inme alt grubu arasında ACE I/D ve AT1R (A1166C) polimorfizmlerinin dağılımı açısından farklılık bulunmadı. Sonuç: Çalışmamızda Trakya bölgesinde yaşayan insanlarda ACE I/D ve AT1R (A1166C) gen polimorfizmlerinin iskemik inme gelişmesinde genetik risk faktörleri olmadıkları belirlendi.

Keywords:

ACE I/D gene polymorphism; AT1R (A1166C) gene polymorphism; ischemic stroke; renin-angiotensin system,

PDF

___

Thiel B, Weder AB. Genes for Essential Hypertension: Hype, Help, or Hope? J Clin Hypertens 2000;2:187-93.
Rice GI, Foy CA, Grant PJ. Angiotensin converting enzyme and angiotensin II type 1-receptor gene polymorphisms and risk of ischaemic heart disease. Cardiovasc Res 1999;41:746-53.
Taniguchi I, Yamazaki T, Wagatsuma K, Kurusu T, Shimazu Y, Takikawa K, et al. The DD genotype of angiotensin converting enzyme polymorphism is a risk factor for coronary artery disease and coro- nary stent restenosis in Japanese patients. Jpn Circ J 2001;65:897-900.
Araşjo MA, Goulart LR, Cordeiro ER, Gatti RR, Menezes BS, Lourenço C, et al. Genotypic interac- tions of renin-angiotensin system genes in myocar- dial infarction. Int J Cardiol 2005;103:27-32.
Sharma P. Meta-analysis of the ACE gene in ischaemic stroke. J Neurol Neurosurg Psychiatry 1998;64:227-30.
Hong SH, Park HM, Ahn JY, Kim OJ, Hwang TS, Oh D, et al. ACE I/D polymorphism in Korean patients with ischemic stroke and silent brain infarction Acta Neurol Scand 2008;117:244-9.
Tuncer N, Tuglular S, Kiliç G, Sazci A, Us O, Kara I. Evaluation of the angiotensin-converting enzyme insertion/deletion polymorphism and the risk of ischaemic stroke. J Clin Neurosci 2006;13:224-7.
Buraczynska M, Ksiazek P, Drop A, Zaluska W, Spasiewicz D, Ksiazek A. Genetic polymorphisms of the renin-angiotensin system in end-stage renal disease. Nephrol Dial Transplant 2006;21:979-83.
Matsubara M. Genetic determination of human essen- tial hypertension. Tohoku J Exp Med 2000;192:19-33.
MacGregor GA, Markandu ND, Roulston JE, Jones JC, Morton JJ. Maintenance of blood pressure by the renin-angiotensin system in normal man. Nature 1981;291:329-31.
de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T. International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 2000;52:415-72.
Soubrier F, Hubert C, Testut P, Nadaud S, Alhenc- Gelas F, Corvol P. Molecular biology of the angio- tensin I converting enzyme: I. Biochemistry and structure of the gene. J Hypertens 1993;11:471-6.
Ehlers MR, Riordan JF. Angiotensin-converting enzyme: new concepts concerning its biological role. Biochemistry 1989;28:5311-8.
Burns KD. Angiotensin II and its receptors in the diabetic kidney. Am J Kidney Dis 2000;36:449-67.
Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 2000;52:11-34.
Takayanagi R, Ohnaka K, Sakai Y, Nakao R, Yanase T, Haji M, et al. Molecular cloning, sequence analysis and expression of a cDNA encoding human type- 1 angiotensin II receptor. Biochem Biophys Res Commun 1992;183:910-6.
Furuta H, Guo DF, Inagami T. Molecular cloning and sequencing of the gene encoding human angiotensin II type 1 receptor. Biochem Biophys Res Commun 1992;183:8-13.
Griendling KK, Lassègue B, Alexander RW. The vas- cular angiotensin (AT1) receptor. Thromb Haemost 1993;70:188-92.
Fluharty SJ, Reagan LP, Yee DK. The angiotensin type 1 and type 2 receptor families. Siblings or cousins? Adv Exp Med Biol 1995;377:193-215.
Hubert C, Houot AM, Corvol P, Soubrier F. Structure of the angiotensin I-converting enzyme gene. Two alternate promoters correspond to evolutionary steps of a duplicated gene. J Biol Chem 1991;266:15377-83.
Mattei MG, Hubert C, Alhenc-Gelas F, Roeckel N, Corvol P, Soubrier F. Angiotensin-I converting enzyme gene is on chromosome 17. Cytogenet Cell Genet 1989; 51:1041-5.
Szpirer C, Rivière M, Szpirer J, Levan G, Guo DF, Iwai N, et al. Chromosomal assignment of human and rat hypertension candidate genes: type 1 angio- tensin II receptor genes and the SA gene. J Hypertens 1993;11:919-25.
Bonnardeaux A, Davies E, Jeunemaitre X, Féry I, Charru A, Clauser E, et al. Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension 1994;24:63-9.
Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymor- phism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86:1343-6.
Schmidt R, Schmidt H, Fazekas F, Schumacher M, Niederkorn K, Kapeller P, et al. Apolipoprotein E polymorphism and silent microangiopathy-related cerebral damage. Results of the Austrian Stroke Prevention Study. Stroke 1997;28:951-6.
Saver J, Tamburi T. Genetics of cerebrovascular dis- ease. In: Pulst SM, editor. Neurogenetics. 1st ed. New York: Oxford University Press; 2000. p. 403-32.
Szolnoki Z. Evaluation of the interactions of com- mon genetic mutations in stroke. Methods Mol Med 2005;104:241-50.
Stewart JA, Dundas R, Howard RS, Rudd AG, Wolfe CD. Ethnic differences in incidence of stroke: prospec- tive study with stroke register. BMJ 1999;318:967-71.
Sacco RL. Newer risk factors for stroke. Neurology 2001;57(5 Suppl 2):S31-4.
Szolnoki Z, Melegh B. Gene-gene and gene-environ- ment interplay represent specific susceptibility for different types of ischaemic stroke and leukoaraiosis. Curr Med Chem 2006;13:1627-34.
Güldiken B, Özkan H, Kabayel L. Akut iskemik inmede ortalama trombosit hacmi ve periferik kan hücre sayısı yanıtı. Trakya Üniv Tıp Fak Derg 2008;25:130-5.
Rigat B, Hubert C, Corvol P, Soubrier F. PCR detec- tion of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1). Nucleic Acids Res 1992;20:1433.
Shanmugam V, Sell KW, Saha BK. Mistyping ACE heterozygotes. PCR Methods Appl 1993;3:120-1.
van Ittersum FJ, de Man AM, Thijssen S, de Knijff P, Slagboom E, Smulders Y, et al. Genetic polymor- phisms of the renin-angiotensin system and com- plications of insulin-dependent diabetes mellitus. Nephrol Dial Transplant 2000;15:1000-7.
Berge KE, Berg K. Polymorphisms at the angio- tensinogen (AGT) and angiotensin II type 1 receptor (AT1R) loci and normal blood pressure. Clin Genet 1998;53:214-9.
Mettimano M, Lanni A, Migneco A, Specchia ML, Romano-Spica V, Savi L. Angiotensin-related genes involved in essential hypertension: allelic distribu- tion in an Italian population sample. Ital Heart J 2001;2:589-93.
Gao X, Yang H, ZhiPing T. Association studies of genetic polymorphism, environmental factors and their interaction in ischemic stroke. Neurosci Lett 2006;398:172-7.
Szolnoki Z, Maasz A, Magyari L, Horvatovich K, Farago B, Somogyvari F, et al. Coexistence of angio- tensin II type-1 receptor A1166C and angiotensin- converting enzyme D/D polymorphism suggests susceptibility for small-vessel-associated ischemic stroke. Neuromolecular Med 2006;8:353-60.
Henskens LH, Kroon AA, van der Schouw YT, Schiffers PM, Grobbee DE, de Leeuw PW, et al. Renin-angiotensin system and nitric oxide synthase gene polymorphisms in relation to stroke. Am J Hypertens 2007;20:764-70.
Banerjee I, Gupta V, Ganesh S. Association of gene polymorphism with genetic susceptibility to stroke in Asian populations: a meta-analysis. J Hum Genet 2007;52:205-19.
Pera J, Slowik A, Dziedzic T, Wloch D, Szczudlik A. ACE I/D polymorphism in different etiologies of ischemic stroke. Acta Neurol Scand 2006;114:320-2.