Türk çiftlerde infertilite ve metilentetrahidrofolat redüktaz genotipleri arasındaki ilişki

Yıl 2023, Cilt: 48 Sayı: 1, 117 - 126, 31.03.2023

Halil İbrahim Pazarbaşı , Bertan Yılmaz , İbrahim Ferhat Ürünsak , Nurşen Keser , Hatice Korkmaz Güvenmez

https://doi.org/10.17826/cumj.1193382

Öz

Amaç: Açıklanamayan infertilite, infertil çiftlerin %15’inde görülen ve konvansiyonel tetkiklerle sebebi tespit edilemeyen bir durumdur. Literatürde, erkek veya kadınlarda methylentetrahydrofolate reductase gen polimorfizmleri (MTHFR C677T ve A1298C) ve açıklanamayan kısırlık arasında ilişki bulunduğunu gösteren çalışmalar mevcuttur. Çalışmamızda MTHFR genindeki C677T ve A1298C polimorfizmleri ile açıklanamayan infertilite arasındaki ilişkinin araştırılması amaçlanmıştır.
Gereç ve Yöntem: Açıklanamayan infertilite tanısı alan çiftler ve sağlıklı kontrollerde MTHFR geninin iki yaygın polimorfizmi (C677T polimorfizmi için n=57 birey; A1298C polimorfizmi için n=62 birey) multiplex PCR amplifikasyon/ligasyon ürünlerinin SNP (Tek nükleotid polimorfizmi) analizi yöntemi ile çalışılmıştır. Çukurova Üniversitesi, Balcalı Hastanesi Merkez Laboratuvarında homosistein düzeyleri (serumda) human hcy ELISA kiti ile, folat değerleri ise Beckman coulter Unicel DxI 800 kemilüminesans test kiti ile belirlendi.
Bulgular: Çalışmamızda, açıklanamayan infertilite ve kontrol gruplarında kadın ve erkek cinsiyetleri arasında MTHFR C677T polimorfizminin genotip ve allel sıklığı açısından istatistiksel olarak anlamlı bir fark bulunmamıştır. A1298C polimorfizmi açısından CC genotip oranlarının açıklanamayan infertilite tanısı almış erkeklerde (%7) kontrol (%19) grubuna göre daha düşük ve istatistiki olarak anlamlı olduğu bulunmuştur. İnfertil ve kontrol grupları arasında serum folik asit ve homosistein düzeyleri karşılaştırıldığında; MTHFR C677T heterozigot bireylerin folat ve homosistein değerleri arasında; MTHFR C677T normal bireylerin homosistein değerleri arasında; MTHFR A1298C heterozigot, normal ve homozigot bireylerin homosistein değerleri arasında; kadın infertil ve kontrol gruplarında MTHFR C677T heterozigot ve normal bireylerin folat değerleri arasında; MTHFR C677T normal bireylerin homosistein değerleri arasında; MTHFR A1298C heterozigot ve normal bireylerin folat değerleri arasında istatistiki olarak önemli fark bulunmuştur.
Sonuç: Açıklanamayan infertilitenin etyopatogenezinde hala bilinmeyen noktalar bulunmaktadır. Folat/homosistein bulgularının çalışılan polimorfizmler ile ilişkisi net değildir. Çalışmamızın sonuçları, MTHFR A1298C polimorfizmi ve erkek fertilite problemleri arasındaki ilişkiyi desteklemektedir.

Anahtar Kelimeler

Açıklanamayan infertilite, MTHFR polimorfizmleri, A1298C, C677T, Folat metabolizması

Destekleyen Kurum

Çukurova Üniversitesi Araştırma Projeleri Birimi

Proje Numarası

FYL-2014-2830

Teşekkür

Hastaların folat ve homosistein değerlerinin çalışılmasında Prof.Dr. Özlem Görüroğlu Öztürk ve Prof.Dr. Salih Çetiner'e katkılarından ötürü teşekkür ederiz.

Association of infertility and methylenetetrahydrofolate reductase genotypes in Turkish couples

Öz

Purpose: Infertility is described as unexplained when all of the tests of a basic infertility evaluation return within normal limits and present in 15% of infertile couples. Some studies indicate that there is an association between methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) mutations and unexplained infertility in male or female grown adults. The objective of this study was to analyze the distributions of MTHFR’s C677T and A1298C genotypes in couples with unexplained fertility problems (UFP) and healthy controls.
Materials and Methods: Two common variants C677T and A1298C of the MTHFR gene were screened in infertile couples (n =60 for C677T polymorphism; n=62 for A1298C polymorphism) and controls from the Cukurova region of Turkey. C677T and A1298C mutations in the MTHFR gene were detected by the SNP analysis (Fragment analysis) kit of the multiplex PCR amplification/ligation products. Homocysteine levels (in serum) were determined by the human hcy ELISA kit and folate values were determined by the Beckman coulter Unicel DxI 800 chemiluminescence test kit at the Central Laboratory of Balcali Hospital in Cukurova University.
Results: In this study, an association between unexplained infertility and MTHFR C677T polymorphism was not found. However, we found an association between MTHFR A1298C polymorphism and males with UFP (%7) and controls (%19). A statistically significant difference was observed between the infertile and control groups regarding i) the folate and homocysteine values of MTHFR C677T heterozygous individuals; ii) the homocysteine values of the MTHFR C677T normal individuals; iii) the homocysteine values of MTHFR A1298C heterozygous, normal and homozygous individuals; iv) the MTHFR C677T heterozygous and normal individuals; v) the homocysteine values of MTHFR C677T normal individuals; vi) the folate values of the MTHFR A1298C heterozygous and normal individuals.
Conclusion: The etiopathogenesis of unexplained infertility remains largely unexplored. However, the relationship of the folate/homocysteine findings with the MTHFR polymorphisms under study is not clear. The results of our study support a relationship between the MTHFR A1298C polymorphism and male fertility problems.

Anahtar Kelimeler

Unexplained infertility, MTHFR polymorphisms, A1298C, C677T, folate metabolism

Proje Numarası

FYL-2014-2830

Kaynakça

• Herodež ŠS, Zagradišnik B, ErjavecŠkerget A, Zagorac A, Takač I, Vlaisavljevıč V et al. MTHFR C677T and A1298C genotypes and haplotypes in Slovenian couples with unexplained infertility problems and in embryonıc tissues from spontaneous abortions. Balkan J Med Genet. 2013;16:31-40.
• Smith S, Pfiefer SM, Collins J. Diagnosis and management of female infertility. JAMA. 2003;290:1767-70.
• Mutlu MF, Bastu E, Oktem M. Unexplained infertility: A current overwiew. Gazi Medical Journal. 2013;24(1).
• Ozpak L, Pazarbasi A. Cytogenetics of male infertility. Archives Medical Review Journal. 2011;20:230-45.
• Mark HFL, Sigman M. Cytogenetics of male infertility. Medical Cytogenetics (Ed. HFL Mark):247-73. New York, Marcel Dekker, 2000.
• Guenther BDF, Sheppard CA, Tran P, Rozen R, Matthews RG, Ludwig ML. The structure and properties of methylenetetrahydrofolate reductase from escherichia coli suggest how folate ameliorates human hyperhomocysteinemia. Nat Struct Mol Biol. 1999;6:359-65
• Yamada K, Chen Z, Rozen R, Matthews RG. Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. Proc Natl Acad Sci U S A. 2001;98:14853-8.
• Eggermann T, Schwanitz G. Abnormal folate metabolism and maternal risk for down syndrome. In Genetics and Etiology of Down Syndrome (Ed S Dey):97-107. Rijeka, Croatia, InTech, 2011.
• Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10;1:111-13.
• Van Der Put NM, Gabreëls F, Stevens EM, Smeitink JA, TrijbelsFJ, Eskes TK. et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998;5:1044-51.
• Adıguzel FI, Adıguzel C, Seyfettinoğlu S, Urunsak IF. Açıklanamayan infertilite etiyolojisinde olası risk faktörü olarak herediter trombofilinin yeri. Bakırköy Tıp Dergisi. 2015;11:162-66.
• Park JH, Lee HCh, Jeong YM, Chung TG, Kim HJ, Kim NK et al. MTHFR C677T polymorphism associates with unexplained infertile male factors. J Assist Reprod Genet. 2005;22:361-68.
• Wong WY, Merkus HM, Thomas CM, Menkveld R, Zielhuis GA, Steegers-Theunissen RP. Effects of folic acid and zincsulfate on male factor subfertility: A double-blind, randomized, placebo-controlled trial. Fertil Steril. 2002;77:491-98.
• Fatini C, Conti L, Turillazzi V, Sticchi E, Romagnuolo I, Milanini MN. et al. Unexplained infertility: Association with inherited thrombophilia. Thromb Res. 2012;129:e185-e188.
• Letsky EA, Swiet M. Maternal hemostasis coagulation problems of pregnancy in; Thrombosis and Hemorrhagie. (Edts: Loscalzo J, Schafer AI) Blackwell Scientific Publications. 1994:965-98.
• Brigden ML. The hypercoagulable state. Who, how, and when to test and treat. Postgrad Med. 1997;101:249-62.
• Ridker PM, Miletich JP, Buring JE, Ariyo AA, Price DT, Manson JE et al. Factor V leiden mutation as a risk factor for recurrent pregnancy loss. Ann Intern Med. 1998; 128:1000-3.
• Casadei L, Puca F, Privitera L, Zamaro V, Emidi E. Inherited thrombophilia in infertile women: implication in unexplained infertility. Fertil Steril. 2010;94:755-7.
• Singh K, Singh SK, Raman R. MTHFR A1298C polymorphism and idiopathic male infertility. J Postgrad Med. 2010;56:267-9.
• Wu W, Shen O, Qin Y, Niu X, Lu C, XiaY et al. Idiopathic male infertility is strongly associated with aberrant promoter methylation of methylenetetrahydrofolate reductase (MTHFR). PloS One. 2010;5:e13884.
• Coulam CB, Jeyendran RS. Thrombophilic gene polymorphisms are risk factors for unexplained infertility. Fertil Steril. 2009;91:1516–7.
• Rawlins ND, Barrett AJ. Evolutionary families of peptidases. Biochem J. 1993;290:205–18.
• Coulam CB, Jeyendran RS, Fishel LA, Roussev RG. Multiple thrombophilic gene mutations are risk factors for implantation failure. Reprod Biomed Online. 2006;12:322–7.
• Goodman CS, Coulam CB, Jeyendran RS, Acosta VA, Roussev R. Which thrombophilic gene mutations are risk factors for recurrent pregnancy loss? Am J Reprod Immunol. 2006;56:230–6.
• Coulam CB, Wallis D, Weinstein J, Dasgupta DS, Jeyendran, RS. Thrombophilic gene mutations among patients experiencing recurrent miscarriage and deep vein thrombosis. Am J Reprod Immunol. 2008;60:426-431.
• Bianca S, Barrano B, Cutuli N, Indaco L, Cataliotti A, Milana G. et al. Unexplained infertility and inherited thrombophilia. Fertil Steril. 2009;92;1:e4.
• Botto LD, Yang Q. 5,10-methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol. 2000;151:862–77.
• Many A, Schrieber L, Rosner S, Lessing JB, Eldor A, Kupferminc MJ. Pathologic features of the placenta in women with severe pregnancy complications and thrombophilia. Obstet Gynecol. 2001;98:1041–4.
• Axelrod HR. Altered trophoblast functions in implantation-defective mouse embryos. Dev Biol. 1985;108:185–90.
• Aflalo ED, Sod-Moriah UA, Potashnik G, Har-Vardi I. Differences in the implantation rates of rat embryos developed in vivo and in vitro: possible role for plasminogen activators. Fertil Steril. 2004; 81:780–5.
• Nelen Wl, Blom HJ, Thomas CM, Steegers EA, Boers CH, Eskes, TK. Methylenetetrahydrofolate reductase polymorphism affects the change in homocysteine and folate concentrations resulting from low dose folic acid supplementation in women with unexplained recurrent miscarriages. J Nutr. 1998;128:1336–41.
• Kallen B. Use of folic acid supplemantation and risk for dizygotic twinning. Obstet Gynecol Surv. 2005;60:212–4.