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The association between cardiovascular disease gene mutations and recurrent pregnancy loss in the Lebanese population

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Abstract

Recurrent pregnancy loss (RPL) is a problem affecting up to 5% of women of childbearing age due to many factors. Studies have shown that RPL and cardiovascular disease (CVD) may have shared risk factors. We compared the prevalence of 12 cardiovascular disease related gene mutations in patients with a history of RPL to normal controls in a major tertiary care center in Lebanon. The CVD StripAssay (ViennaLab, Austria) was used to analyze the CVD genes on 70 women with RPL history as part of the initial routine workup for recurrent miscarriage at the American University of Beirut Medical Center. The obtained results were compared with data of controls from the Lebanese population using Fisher’s exact test and Chi square analysis. Two genes of the CVD panel demonstrated a strong relationship with RPL, including, MTHFR (C677T homozygosity, A1298C homozygosity, and compound heterozygosity for C677T and A1298C) and Factor II (heterozygosity for G20210A). Moreover, a protective role of positive APO-E3 isoform was observed. This study is the first in the Lebanese population in associating RPL with a large panel of CVD related genes.

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References

  1. Buchholz T, Lohse P, Rogenhofer N, Kosian E, Pihusch R, Thaler CJ (2003) Polymorphisms in the ACE and PAI-1 genes are associated with recurrent spontaneous miscarriages. Hum Reprod 18(11):2473–2477

    Article  CAS  PubMed  Google Scholar 

  2. Ciftdoğan DY, Coşkun S, Ulman C, Tikiz H (2009) The factor V G1691A, factor V H1299R, prothrombin G20210A polymorphisms in children with family history of premature coronary artery disease. Coron Artery Dis 20(7):435–439

    Article  PubMed  Google Scholar 

  3. Contois JH, McConnell JP, Sethi AA, Csako G, Devaraj S, Hoefner DM, Warnick GR (2009) Apolipoprotein B and cardiovascular disease risk: position statement from the AACC lipoproteins and vascular diseases division working group on best practices. Clin Chem 55(3):407–419

    Article  CAS  PubMed  Google Scholar 

  4. Coulam CB, Jeyendran RS, Fishel LA, Roussev RG (2006) Multiple thrombophilic gene mutations rather than specific gene mutations are risk factors for recurrent miscarriage. Am J Reprod Immunol 55(5):360–368

    Article  CAS  PubMed  Google Scholar 

  5. Eichner JE, Dunn ST, Perveen G, Thompson DM, Stewart KE, Stroehla BC (2002) Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol 155(6):487–495

    Article  PubMed  Google Scholar 

  6. Garcia-Enguidanos A, Calle ME, Valero J, Luna S, Dominguez-Rojas V (2002) Risk factors in miscarriage: a review. Eur J Obstet Gynecol Reprod Biol 102(2):111–119

    Article  CAS  PubMed  Google Scholar 

  7. Gardemann A, Lohre J, Katz N et al (1999) The 4G4G genotype of the plasminogen activator inhibitor 4G/5G gene polymorphism is associated with coronary atherosclerosis in patients at high risk for this disease. Thromb Haemost 82(3):1121–1126

    CAS  PubMed  Google Scholar 

  8. Goodman CS, Coulam CB, Jeyendran RS, Acosta VA, Roussev R (2006) Which thrombophilic gene mutations are risk factors for recurrent pregnancy loss? Am J Reprod Immunol 56(4):230–236

    Article  CAS  PubMed  Google Scholar 

  9. Goyette P, Sumner JS, Milos R, Duncan AMV, Rosenblatt DS, Matthews RG, Rozen R (1994) Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 7:195–200

    Article  CAS  PubMed  Google Scholar 

  10. Greene DG, Dunlevy LP, Copp. AJ (2003) Homocysteine is embryotoxic but does not cause neural tube defects in mouse embryos. Anat Embryol 206(3):185–191

    Article  CAS  PubMed  Google Scholar 

  11. Hamdi K, Vaezi M, Dagigazar B, Sadagiani MM, Farzadi L, Pashaei-Asl M (2012) Association between thrombophilia and repeated assisted reproductive technology failures. Adv Pharm Bull 2(2):233–237

    PubMed  PubMed Central  Google Scholar 

  12. Hanis CL, Hewett-Emmett D, Douglas TC et al (1991) Effects of the apolipoprotein E polymorphism on levels of lipids, lipoproteins, and apolipoproteins among Mexican-Americans in Starr County, Texas. Arterioscler Thromb 11(2):362–370

    Article  CAS  PubMed  Google Scholar 

  13. Iacoviello L, Burzotta F, Di Castelnuovo A et al (1998) The 4G/5G polymorphism of PAI-1 promoter gene and the risk of myocardial infarction: a meta-analysis. Thromb Haemost 80(6):1029–1030

    CAS  PubMed  Google Scholar 

  14. Jofre-Monseny L, Minihane AM, Rimbach G (2008) Impact of apoE genotype on oxidative stress, inflammation and disease risk. Mol Nutr Food Res 52(1):131–145

    Article  CAS  PubMed  Google Scholar 

  15. Kohler HP, Grant PJ (1999) The role of factor XIIIVal34Leu in cardiovascular disease. Q J Med 92(2):67–72

    Article  CAS  Google Scholar 

  16. Korkmazer E, Ustunyurt E, Tekin B, Cilingir O (2013) Study on potential role of apolipoprotein E in recurrent pregnancy loss. Exp Ther Med 5(5):1408–1410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lane DA, Grant PJ (2000) Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood 95(5):1517–1532

    CAS  PubMed  Google Scholar 

  18. Li J, Chen Y, Wu H, Li L (2014) Apolipoprotein E (Apo E) gene polymorphisms and recurrent pregnancy loss: a meta-analysis. J Assist Reprod Genet 31(2):139–148

    Article  PubMed  Google Scholar 

  19. Mahfouz RAR, Sabbagh AS, Shammaa DMR, Otrock ZK, Zaatari GS, Taher AT (2008) Factor XIII gene V34L mutation in the Lebanese population: another unique feature in this community. Mol Biol Rep 35(3):375–378

    Article  CAS  PubMed  Google Scholar 

  20. Mahfouz RAR, Sabbagh AS, Zahed LF, Mahfoud ZR, Kalmoni RF, Otrock ZK, Taher AT, Zaatari GS (2006) Apolipoprotein E gene polymorphism and allele frequencies in the Lebanese population. Mol Biol Rep 33(2):145–149

    Article  CAS  PubMed  Google Scholar 

  21. Mahley RW (1988) Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240(4852):622–630

    Article  CAS  PubMed  Google Scholar 

  22. Oliver-Williams CT, Heydon EE, Smith GCS, Woodet AM (2013) Miscarriage and future maternal cardiovascular disease: a systematic review and meta-analysis. Heart 99:1636–1644

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ozdemir O, Yenicesu GI, Silan F, Köksal B, Atik S, Ozen F, Göl M, Cetin A (2012) Recurrent pregnancy loss and its relation to combined parental thrombophilic gene mutations. Genet Test Mol Biomark 16(4):279–286

    Article  CAS  Google Scholar 

  24. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM (1996) A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 88:3698–3703

    CAS  PubMed  Google Scholar 

  25. Refsum H, Ueland PM, Nygard O, Vollset SE (1998) Homocysteine and cardiovascular disease. Annu Rev Med 49:31–62

    Article  CAS  PubMed  Google Scholar 

  26. Rosendaal FR, Siscovick DS, Schwartz SM, Beverly RK, Psaty BM, Longstreth WT Jr, Raghunathan TE, Koepsell TD, Reitsma PH (1999) Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction young women. Blood 89(8):2817–2821

    Google Scholar 

  27. Sabbagh AS, Daher RT, Otrock ZK, Abdel Khalek RN, Zaatari GS, Mahfouz RAR (2007) ApoB-100 R3500Q mutation in the Lebanese population: prevalence and historical review of the literature. Mol Biol Rep 34(4):267–270

    Article  CAS  PubMed  Google Scholar 

  28. Sabbagh AS, Ibrahim G, Kanaan Z, Shammaa DMR, Abdel Khalek R, Ghasham M, Greige L, Mahfouz RAR (2009) Prevalence of the prothrombin G20210A polymorphism in the Lebanese population: use of a reverse hybridization strip assay approach. Mol Biol Rep 36(2):399–403

    Article  CAS  PubMed  Google Scholar 

  29. Sabbagh AS, Mahfoud Z, Taher A, Zaatari G, Daher R, Mahfouz RAR (2008) High prevalence of MTHFR gene A1298C polymorphism in Lebanon. Genet Test 12(1):75–80

    Article  CAS  PubMed  Google Scholar 

  30. Sabbagh AS, Otrock ZK, Mahfoud ZR, Zaatari GS, Mahfouz RAR (2007) Angiotensin-converting enzyme gene polymorphism and allele frequencies in the Lebanese population: prevalence and review of the literature. Mol Biol Rep 34(1):47–52

    Article  CAS  PubMed  Google Scholar 

  31. Sabbagh AS, Taher AT, Zaatari GS, Mahfouz RAR (2007) Gene frequencies of the HPA-1 platelet antigen alleles in the Lebanese population. Transfus Med 17:473–478

    Article  CAS  PubMed  Google Scholar 

  32. Shammaa DMR, Sabbagh AS, Taher AT, Zaatari GS, Mahfouz RAR (2008) Frequency distribution of the G/A alleles of the b-fibrinogen gene in the Lebanese population. Mol Biol Rep 35(3):307–311

    Article  CAS  PubMed  Google Scholar 

  33. Shammaa DMR, Sabbagh AS, Taher AT, Zaatari GS, Mahfouz RAR (2008) Plasminogen activator inhibitor-1 (PAI-1) gene 4G/5G alleles frequency distribution in the Lebanese population. Mol Biol Rep 35(3):453–457

    Article  CAS  PubMed  Google Scholar 

  34. Shibuya M (2011) Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis. A crucial target for anti- and Pro-angiogenic therapies. Genes Cancer 2(12):1097–1105

    Article  PubMed  PubMed Central  Google Scholar 

  35. Siest G, Pillot T, Régis-Bailly A et al. (1995) Apolipoprotein E: an important gene and protein to follow in laboratory medicine. Clin Chem 41(8):1068–1086

    CAS  PubMed  Google Scholar 

  36. Stec JJ, Silbershatz H, Tofler GH, Matheney TH, Sutherland P, Lipinska I, Massaro JM, Wilson PFW, Muller JE, D’Agostino RB (2000) Association of fibrinogen with cardiovascular risk factors and cardiovascular disease in the Framingham offspring population. Circulation 102(14):1634–1638

    Article  CAS  PubMed  Google Scholar 

  37. Steed MM, Tyagi SC (2011) Mechanisms of cardiovascular remodeling in hyperhomocysteinemia. Antioxid Redox Signal 15(7):1927–1943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. The Practice Committee of the American Society for Reproductive Medicine Obesity and Reproduction (2008) An educational bulletin. Fertil Steril 90(5 Suppl):S21–S29

    Google Scholar 

  39. Varga EA, Sturm AC, Misita CP, Moll S (2005) Homocysteine and MTHFR mutations relation to thrombosis and coronary artery disease. Circulation 111(19):e289–e293

    Article  CAS  PubMed  Google Scholar 

  40. Wagner MM, Bhattacharya S, Visser J et al (2015) Association between miscarriage and cardiovascular disease in a Scottish cohort. Heart 104(8):1954–1960

    Article  Google Scholar 

  41. Weiss EJ, Bray PF, Tayback M, Schulman SP, Kickler TS, Becker LC et al (1996) A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med 334(17):1090–1094

    Article  CAS  PubMed  Google Scholar 

  42. Zaatari GS, Otrock ZK, Sabbagh AS, Mahfouz RAR (2006) Prevalence of factor V R2 (H1299R) polymorphism in the Lebanese population. Pathology 38(5):442–444

    Article  CAS  PubMed  Google Scholar 

  43. Zonouzi AP, Chaparzadeh N, Ghorbian S et al (2013) The association between thrombophilic gene mutations and recurrent pregnancy loss. J Assist Reprod Genet 30(10):1353–13593

    Article  Google Scholar 

  44. Zonouzi AP, Farajzadeh D, Bargahi N, Farajzadeh M (2014) Apolipoprotein E genotyping in women with recurrent pregnancy loss: an in silico and experimental hybrid study. Gene 549(2):209–213

    Article  Google Scholar 

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Correspondence to Rami Mahfouz.

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Research involving human participants and all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was waived by the Intuitional Review Board of the American University of Beirut Medical Center.

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This article does not contain any studies on humans or animals. It was a retrospective review of data.

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El Achi, H., Awwad, J., Abou Daya, S. et al. The association between cardiovascular disease gene mutations and recurrent pregnancy loss in the Lebanese population. Mol Biol Rep 45, 911–916 (2018). https://doi.org/10.1007/s11033-018-4237-1

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  • DOI: https://doi.org/10.1007/s11033-018-4237-1

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