Association between thrombophilia gene polymorphisms and recurrent pregnancy loss risk in the Iranian population
Association between thrombophilia gene polymorphisms and recurrent pregnancy loss risk in the Iranian population
samaneh heidarzadeh,1Razieh Bigdeli ,2Vahid Asgary,3,*
1. Research and Development Laboratory, Javid Biotechnology Institute, Tehran, Iran 2. Research and Development Laboratory, Javid Biotechnology Institute, Tehran, Iran 3. Research and Development Laboratory, Javid Biotechnology Institute, Tehran, Iran
Introduction: Miscarriage is the most common complication in pregnancy. The pathophysiology of recurrent pregnancy loss (RPL) is a complex problem and poorly understood. Many believe that RPL is influenced by different factors such as abnormalities in chromosomes, anatomic, endocrine, immune defects, and also infections (Garcia-Enguidanos et al. 2002; Ford and Schust 2009; Jaleh et al. 2011). Thrombophilia is one of the major cause of RPL (Buchholz and Thaler 2003; Di Micco et al. 2007; JeddiTehrani et al. 2010). This compelling fact that patients who have inherited thrombophilic abnormalities show higher risks of RPL, has encouraged researchers to investigate patients with RPL, and look for its relation to thrombophilic polymorphism frequencies (Coulam et al. 2006) . During pregnancy, changes in the body systems of mother resulting in changes in the homeostasis results in the hypercoagulable state of pregnancy. As a result the risk of thrombophilia becomes greater which can reflect many genetic factors such as polymorphisms which later affect the coagulation system and folate metabolism pathway (Goodman et al. 2006). Genetic researchers worldwide are trying to look for RPL candidate genes and have performed various experiments on many different genetic variants. The main focus of these experiments is on the mutations that cause thrombophilia and it is thought that it is inherited maternally. But, it is still controversial whether thrombophilic gene mutations are an important factor in RPL (Brenner 1999; Blanco-Molina et al. 2007; Yenicesu et al. 2010). Considering the importance of the problem thrombophilia in pregnant women and its association with recurrent pregnancy loss (RPL), analysis of polymorphisms of genes involved in thrombophilia can be useful.
Methods: We investigated the frequency and association between ten polymorphisms of seven thrombophilia genes and RPL in an Iranian population. This case-control study was conducted on 200 women with recurrent pregnancy loss and also on 200 women with at least one successful pregnancy as the control group. Using PCR-RFLP, DNA from samples were analyzed for carrying A5279G, A4070G, and FV Leiden of factor V; FXIII (Val34Leu); FII (A20210G); BF (−455 G⁄A); ITGB3 (1565T⁄C); 677C/T and 1298A/C of MTHFR; and PAI-1 (−675 I/D, 5G/4G) polymorphisms.
Results: In this study, 200 healthy people as controls and 200 patients were examined and in some cases, the results showed different results compared with studies conducted in different populations with respect to relation between thrombophilia gene polymorphisms and the risk of RPL.
The BF(−455 G⁄A), MTHFR (677 C⁄T, 1298A⁄ C), PAI-1 (−675 I/D,4G⁄ 5G), FV Leiden, FV (A5279G), FXIII (Val34Leu) polymorphisms, which had shown positive relation, and ITGB3 1565T⁄C were the polymorphisms with negative relation to RPL. But in this study it is indicated that there is no significant association between FII (A20210G) and FV (A4070G) polymorphism and RPL. All the data acquired from the RPL patients in this experiment illustrate the importance of screening thrombophilia. Nevertheless, more studies on large-scale populations may be needed to identify novel genetic variants.
Conclusion: In this study, bias is unlikely to be present for the following reasons. First, because all the women were of the same ethnic origin and lived in the same geographic area, variations in the frequency of gene mutations were minimized. Second, interpretation bias was avoided by having the laboratory diagnosis made by technicians who were unaware of the characteristics of the study participants. However, in order to better understand the pathobiology of thrombophilia in RPL disease, further studies are needed on larger scale populations and identify novel genetic variants and the interaction of these variants with each other and the environment.