Elif Funda EMİROĞULARI, Çetin SAATÇİ, Aydın ÜNAL, Yusuf ÖZKUL

ARTERİYO-VENÖZ FİSTÜL TROMBOZU GELİŞEN VE GELİŞMEYEN KRONİK BÖBREK YETMEZLİĞİ OLAN HASTALARDA METİLENTETRAHİDROFOLAT REDÜKTAZ POLİMORFİZMLERİNİN ARAŞTIRILMASI

Metilentetrahidrofolat redüktaz (MTHFR), folat döngüsünde önemli bir rol oynar ve homosistein metabolizmasına katkıda bulunur. MTHFR genindeki bazı mutasyonlar, MTHFR geninin enzim aktivitesinde azalmaya neden olabilir. MTHFR geninde yaygın olarak C677T ve A1298C polimorfizmleri görülür. Bu çalışmada kronik böbrek yetmezlikli (KBY) hastalarda MTHFR C677T ve MTHFR A1298C polimorfizmlerinin etkisi araştırılmıştır. Bu amaçla nedeni bilinmeyen arteriyovenöz fistül trombozu gelişen KBY’li 31 kişi hasta grubu ve fistül tıkanması görülmeyen KBY’li 51 kişi kontrol grubu olarak çalışıldı. Periferal kan örnekleri alınarak DNA izole edildi. MTHFR C677T ve MTHFR A1298C polimorfizmi PCR-RFLP yöntemi ile belirlendi. MTHFR C677T polimorfizminin hasta ve kontrol grubunda normal genotipli birey sayısı sırasıyla 27 (%87.09) ve 44 (%86.27), heterozigot genotipli birey sayısı 4 (%12.90) ve 6 (%11.76) olarak tespit edildi. Hasta grubunda homozigot mutant genotip bulunmazken kontrol grubunda bir kişide (%2) tespit edildi. MTHFR A1298C polimorfizminin hasta ve kontrol grubunda normal genotipli birey sayısı sırasıyla 12 (%38.70) ve 14 (%27.50) olarak; heterozigot genotipli birey sayısı sırasıyla 12 (%38.70) ve 25 (%49), homozigot mutant genotipli birey sayısı 7 (%22.60) ve 12 (%23.50) olarak tespit edildi. Araştırma sonucunda kronik böbrek yetmezlikli hasta ve kontrol grubu arasında MTHFR C677T ve A1298C genotipleri ve allel sıklıkları açından önemli bir fark bulunamadı. Elde edilen bulgular KBY’li hastalarda MTHFR C677T ve MTHFR A1298C polimorfizmlerinin tromboz riskini etkilemediğini işaret etmektedir

Anahtar Kelimeler:

Kronik böbrek yetmezliği, MTHFR, A1298C, C677T

Researching Methylenetetrahydrofolate Reductase Polymorphisms in Chronic Renal Failure Patients with Developing and Non-Devoloping Arterio-Venous Thrombosis

Methylenetetrahydrofolate reductase (MTHFR) plays an important role in the folate cycle and contribures to the metabolism of the aminoacid homocysteine. Some of the mutations in the MTHFR gene cause a decrease in MTHFR activity. Particularly C677T and A1298C mutations in MTHFR gene are two common polymorphisms. The aim of this study is to find out the relationship between MTHFR C677T/A1298C mutations and chronic renal failure patients. Thirty-one chronic renal failure patients with developing arteriovenous thrombosis and 51 chronic renal failure patients with nondeveloping arterio-venous thrombosis were chosen. DNA was extracted from peripheral blood samples of the patients and controls. MTHFR C677T and MTHFR A1298C polymorphisms was identified by PCR (polymerase chain reaction)-RFLP (restriction fragment length polymorphism) methods. MTHFR C677T polymorphism in patients and control group normal genotype was found in 27 (87.09%) and 44 (86.27%), heterozygote genotype 4 (12.90%) and 6 (11.76%). No homozygote subjects were found in patients group but one subject were detected in the control group (2%). MTHFR A1298C polymorphism in patients and control group normal genotype was found in 12 (38.70%) and 14 (27.50%), heterozygote genotype 12 (38.70%) and 25 (49%), homozygote genotype 7 (22.60%) and 12 (23.50%). MTHFR C677T and MTHFR A1298C genotype and allele frequency were not significantly different in patients and control groups with chronic renal failure. As a result, MTHFR C677T and MTHFR A1298C polymorphisms are not a risk factor for thrombosis in chronic renal failure patients

Keywords:

Chronic renal failure, MTHFR, A1298C, C677T,

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Rosenblatt DS. Metyhlenetetrahydrofolate reductase. Clin Invest Med 2001, 24:56-59.
Homberger G, Linnebank M, Winter C, et al. Genomic structure and transcript variants of the human metyhlenetetrahydrofolate reductase gene. Eur J Hum Gen 2000, 8:725-729.
Weisberg I, Tran P, Christensen B, et al. A second genetic polymorphism in metyhlenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 1998, 64:169-172.
Bailey LB, Duhaney RL, Maneval DR, et al. Vitamin B-12 status is inversely associated with plasma homocysteine in young women with C677T and/or A1298C metyhlenetetrahydrofolate reductase polymorphisms. J Nutr 2002, 132:24665-24709.
Bagley PJ, Jacob S. A common mutation in the Metyhlenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells. Med Sci , 95:13217-13220.
Goyette P, Pai A, Milos R, et al. Gene structure of human Mouse metyhlenetetrahydrofolate reductase (MTHFR). Mammalian Genome , 9:652-656. Tonetti C, Burtscher A, Bories D, et al. Metyhlenetetrahydrofolate reductase deficiency in four siblings: A clinical, biochemical and molecular study of the familiy. Am J Med Genet , 91:363-367. Sell SM, Lugemwa PR. Development of a highly accurate, rapid PCR-RFLP genotyping assay for the metyhlenetetrahydrofolate reductase gene. Genet Test 1999, 3:287-289.
Taşçıoğlu N, Taheri S, Saatçi Ç, Özkul Y. Gastrointestinal Sistem Kanserlerinde Metilentetrahidrofolat Redüktaz Geni 677CàT Polimorfizminin İncelenmesi. Erciyes Üniversi- tesi Sağlık Bilimleri Dergisi 2006, 15(1):41-45,
Födinger M, Horl WH, Sunder-Plassman G. Molecular biology of 5,10- methylenetetrahydrofolate reductase. J Nephrol , 13 (1) 20-33. Sharp L, Little J. Polymorphism in genes involved in folate metabolism and colorectal neoplasia: A HuGE Review Am J Epidemiol , 159:423-443. Güleç S, Aras O, Akar E ve ark. MTHFR gene polymorphism and risk of premature myocardial infarction. Clinical Cardiology , 24 (4):281-4. Chauveau P, Chadefaux B, Coude M et al. Hyperhomocysteinemia, a risk factor for atherosclerosis in chronic uremic patients. Kidney Int Suppl 1993, 43:S72-77.
Hultberg B, Andersson A, Arnadottir M. Reduced, free and total fractions of homocysteine and other thiol compounds in plasma from patients with renal failure. Nephron 1995, 70:62-67.
Hörl WH. Genesis of the ureamic syndrome. In: Davison AM, Cameron JS, Grünfeld .IP, Kerr DNS, Ritz E, Winearls CG (eds). Oxford Textbook of Clinical Nephrology. Oxford Medical Publications Oxford 1998, pp 1822
Bostom AG, Lathrop L. Hyperhomocysteinemia in endstage renal disease: Prevalence, etiology, and potential relationship to atherosclerotic outcomes. Kidney Int 1997, 52:10-20.
Couturaud F, Oger E, Abalain JH, et al. Methylenetetrahydrofolate reductase C677T genotype and venous thromboembolic disease. Respiration 2000, 67:657-661.
Vychytil A, Födinger M, Wolf G, et al. Major determinants of hyperhomocysteinemia in peritoneal dialysis patients. Kidney Int 1998, :1775-1782.
Guldener CV, Robinson K. Homocysteine and Renal disease. Sem Thrombos Hemostasis , 26 (3):313-324. Födinger M, Wagner OF, Hörl WH, et al. Recent insights into the molecular genetics of the homocysteine metabolism. Kidney Int Suppl , 59:238-242. Födinger M, Buchmayer H, Heinz G, et al. Effect of MTHFR 1298 A C and MTHFR 677C
T genotypes on total homocysteine, folate, and vitamin B 12 plasma concentrations in kidney graft recipients. J Am Soc Nephrol 2000, :1918-1925.
Dikmen M, Gülel B, Güneş HV ve ark. Akut inme hastalarında risk faktörü olan homosistein düzeyine MTHFR gen polimorfizmlerinin etkisi. Kocatepe Tıp Dergisi, 2004, 5:55-61.
Van Der Put NM, Gabreels F, Stevens EMB, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: An additional risk factor for neural-tube defects. Am J Hum Genet 1998, 62:1044-1051.
Friedman G, Goldschmidt N, Friedlander Y, et al. Common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocystein and folate concentrations. J Nutr 1999, 129:1656
Domagala TB, Adamek L, Nizankowska E, et al. Mutations C677T and A1298C of the 5,10- methylenetetrahydrofolate reductase gene and fasting homocysteine levels are not associated with the increased risk of venous thromboembolic disease. Blood Coagulation and Fibrinolysis 2002, 13:423-431.