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Published in: Archives of Gynecology and Obstetrics 5/2013

01-11-2013 | Reproductive Medicine

Polymorphisms in MTHFR, MTHFD, and PAI-1 and recurrent miscarriage among North Indian women

Authors: Farah Parveen, Moni Tuteja, Suraksha Agrawal

Published in: Archives of Gynecology and Obstetrics | Issue 5/2013

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Abstract

Purpose

The aim of this study was to investigate the association between MTHFR C677T, A1298C, MTHFD G1958A and plasminogen activator inhibitor type 1 (PAI-1) 4G/5G polymorphism among first trimester recurrent miscarriages.

Materials and methods

DNA was extracted from peripheral blood samples from 200 patients and 300 controls. Polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) and sequencing were used to identify the polymorphisms. We have analyzed the frequencies, odds ratio, Hardy–Weinberg equilibrium.

Results

MTHFR C677T, A1298C, and MTHFD G1958A variant alleles were found to be significantly more prevalent in patients than control. However, variant genotype of MTHFR C677T (OR = 2.54; 95 % CI = 1.23–5.24; p value = 0.014), 1298C (OR = 2.23; 95 % CI = 1.09–4.52; p value = 0.028), and MTHFD-1958 showed significant association with pregnancy loss (OR = 2.36; 95 % CI = 1.39–4.02; p value = 0.002). Both MTHFR 677 and MTHFD 1958 showed susceptible effect under recessive model of inheritance. PAI-1 mutations showed no significance.

Conclusion

We observed significant susceptible effects of MTHFR C677T, A1298C, and MTHFD G1958A among RM cases. Our data points toward the multifactorial nature of the recurrent miscarriage as relative contribution of variant genotype of MTHFR C677T is only twofold and further decreased to only onefold, and MTHFD-1958 lost its significance upon meta-analysis.
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Literature
1.
go back to reference Cohn DM, Goddijn M, Middeldorp S, Korevaar JC, Dawood F, Farquharson RG (2010) Recurrent miscarriage and antiphospholipid antibodies: prognosis of subsequent pregnancy. J Thromb Haemost 8(10):2208–2213PubMedCrossRef Cohn DM, Goddijn M, Middeldorp S, Korevaar JC, Dawood F, Farquharson RG (2010) Recurrent miscarriage and antiphospholipid antibodies: prognosis of subsequent pregnancy. J Thromb Haemost 8(10):2208–2213PubMedCrossRef
2.
go back to reference Jauniaux E, Farquharson RG, Christianson OB, Exalto N (2006) Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum Reprod 21(9):2216–2222PubMedCrossRef Jauniaux E, Farquharson RG, Christianson OB, Exalto N (2006) Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum Reprod 21(9):2216–2222PubMedCrossRef
3.
go back to reference Parveen F, Shukla A, Agrawal S (2012) Should factor V Leiden mutation and prothrombin gene polymorphism testing be done in women with recurrent miscarriage from North India? Arch Gynecol Obstet 287(2):375–381PubMedCrossRef Parveen F, Shukla A, Agrawal S (2012) Should factor V Leiden mutation and prothrombin gene polymorphism testing be done in women with recurrent miscarriage from North India? Arch Gynecol Obstet 287(2):375–381PubMedCrossRef
4.
go back to reference Wramsby ML, Sten-Linder M, Bremme K (2000) Primary habitual abortions are associated with high frequency of factor V leiden mutation. Fertil Steril 74(5):987–991PubMedCrossRef Wramsby ML, Sten-Linder M, Bremme K (2000) Primary habitual abortions are associated with high frequency of factor V leiden mutation. Fertil Steril 74(5):987–991PubMedCrossRef
5.
go back to reference Parveen F, Faridi RM, Das V, Tripathi G, Agrawal S (2010) Genetic association of phase I and phase II detoxification genes with recurrent miscarriages among North Indian women. Mol Hum Reprod 16(3):207–214PubMedCrossRef Parveen F, Faridi RM, Das V, Tripathi G, Agrawal S (2010) Genetic association of phase I and phase II detoxification genes with recurrent miscarriages among North Indian women. Mol Hum Reprod 16(3):207–214PubMedCrossRef
6.
go back to reference Sata F, Yamada H, Suzuki K, Saijo Y, Kato EH, Morikawa M et al (2005) Caffeine intake, CYP1A2 polymorphism and the risk of recurrent pregnancy loss. Mol Hum Reprod 11(5):357–360PubMedCrossRef Sata F, Yamada H, Suzuki K, Saijo Y, Kato EH, Morikawa M et al (2005) Caffeine intake, CYP1A2 polymorphism and the risk of recurrent pregnancy loss. Mol Hum Reprod 11(5):357–360PubMedCrossRef
7.
go back to reference Robertson L, Wu O, Langhorne P, Twaddle S, Clark P, Lowe GD et al (2006) Thrombophilia in pregnancy: a systematic review. Br J Haematol 132(2):171–196PubMedCrossRef Robertson L, Wu O, Langhorne P, Twaddle S, Clark P, Lowe GD et al (2006) Thrombophilia in pregnancy: a systematic review. Br J Haematol 132(2):171–196PubMedCrossRef
8.
go back to reference Bokarewa MI, Bremme K, Blombäck M (1996) Arg506-Gln mutation in factor V and risk of thrombosis during pregnancy. Br J Haematol 92(2):473–478PubMedCrossRef Bokarewa MI, Bremme K, Blombäck M (1996) Arg506-Gln mutation in factor V and risk of thrombosis during pregnancy. Br J Haematol 92(2):473–478PubMedCrossRef
9.
go back to reference Cai D, Ning L, Pan C, Liu X, Bu R, Chen X et al (2010) Association of polymorphisms in folate metabolic genes and prostate cancer risk: a case–control study in a Chinese population. J Genet 89(2):263–267PubMedCrossRef Cai D, Ning L, Pan C, Liu X, Bu R, Chen X et al (2010) Association of polymorphisms in folate metabolic genes and prostate cancer risk: a case–control study in a Chinese population. J Genet 89(2):263–267PubMedCrossRef
10.
go back to reference Nelen WL, Bulten J, Steegers EA, Blom HJ, Hanselaar AG, Eskes TK (2000) Maternal homocysteine and chorionic vascularization in recurrent early pregnancy loss. Hum Reprod 15(4):954–960PubMedCrossRef Nelen WL, Bulten J, Steegers EA, Blom HJ, Hanselaar AG, Eskes TK (2000) Maternal homocysteine and chorionic vascularization in recurrent early pregnancy loss. Hum Reprod 15(4):954–960PubMedCrossRef
11.
go back to reference Obwegeser R, Sinzinger HM (1999) Homocysteine—a pathophysiological cornerstone in obstetrical and gynaecological disorders? Hum Reprod Update 5(1):64–72PubMedCrossRef Obwegeser R, Sinzinger HM (1999) Homocysteine—a pathophysiological cornerstone in obstetrical and gynaecological disorders? Hum Reprod Update 5(1):64–72PubMedCrossRef
12.
go back to reference Aflalo ED, Sod-Moriah UA, Potashnik G, Har-Vardi I (2004) Differences in the implantation rates of rat embryos developed in vivo and in vitro: possible role for plasminogen activators. Fertil Steril 81(1):780–785PubMedCrossRef Aflalo ED, Sod-Moriah UA, Potashnik G, Har-Vardi I (2004) Differences in the implantation rates of rat embryos developed in vivo and in vitro: possible role for plasminogen activators. Fertil Steril 81(1):780–785PubMedCrossRef
13.
14.
go back to reference Botto LD, Yang Q (2000) 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol 151(9):862–877PubMedCrossRef Botto LD, Yang Q (2000) 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol 151(9):862–877PubMedCrossRef
15.
go back to reference Sharp L, Little J (2004) Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review. Am J Epidemiol 159(5):423–443PubMedCrossRef Sharp L, Little J (2004) Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review. Am J Epidemiol 159(5):423–443PubMedCrossRef
16.
go back to reference Shi M, Caprau D, Romitti P, Christensen K, Murray JC (2003) Genotype frequencies and linkage disequilibrium in the CEPH human diversity panel for variants in folate pathway genes MTHFR, MTHFD, MTRR, RFC1, and GCP2. Birth Defects Res A Clin Mol Teratol 67(8):545–549PubMedCrossRef Shi M, Caprau D, Romitti P, Christensen K, Murray JC (2003) Genotype frequencies and linkage disequilibrium in the CEPH human diversity panel for variants in folate pathway genes MTHFR, MTHFD, MTRR, RFC1, and GCP2. Birth Defects Res A Clin Mol Teratol 67(8):545–549PubMedCrossRef
17.
go back to reference Govindaiah V, Naushad SM, Prabhakara K, Krishna PC, Radha Rama Devi A (2009) Association of parental hyperhomocysteinemia and C677T methylene tetrahydrofolatereductase (MTHFR) polymorphism with recurrent pregnancy loss. Clin Biochem 42(4–5):380–386PubMedCrossRef Govindaiah V, Naushad SM, Prabhakara K, Krishna PC, Radha Rama Devi A (2009) Association of parental hyperhomocysteinemia and C677T methylene tetrahydrofolatereductase (MTHFR) polymorphism with recurrent pregnancy loss. Clin Biochem 42(4–5):380–386PubMedCrossRef
18.
go back to reference Yenicesu GI, Cetin M, Ozdemir O, Cetin A, Ozen F, Yenicesu C et al (2010) A prospective case–control study analyzes 12 thrombophilic gene mutations in turkish couples with recurrent pregnancy loss. Am J Reprod Immunol 63(2):126–136PubMedCrossRef Yenicesu GI, Cetin M, Ozdemir O, Cetin A, Ozen F, Yenicesu C et al (2010) A prospective case–control study analyzes 12 thrombophilic gene mutations in turkish couples with recurrent pregnancy loss. Am J Reprod Immunol 63(2):126–136PubMedCrossRef
19.
go back to reference Mukhopadhyay R, Saraswathy KN, Ghosh PK (2009) MTHFR C677T and factor V leiden in recurrent pregnancy loss: a study among an endogamous group in North India. Genet Test Mol Biomarkers 13(6):861–865PubMedCrossRef Mukhopadhyay R, Saraswathy KN, Ghosh PK (2009) MTHFR C677T and factor V leiden in recurrent pregnancy loss: a study among an endogamous group in North India. Genet Test Mol Biomarkers 13(6):861–865PubMedCrossRef
20.
go back to reference Settin A, Elshazli R, Salama A, ElBaz R (2011) Methylenetetrahydrofolate reductase gene polymorphisms in Egyptian women with unexplained recurrent pregnancy loss. Genet Test Mol Biomarkers 15(12):887–892PubMedCrossRef Settin A, Elshazli R, Salama A, ElBaz R (2011) Methylenetetrahydrofolate reductase gene polymorphisms in Egyptian women with unexplained recurrent pregnancy loss. Genet Test Mol Biomarkers 15(12):887–892PubMedCrossRef
21.
go back to reference Christensen KE, Rohlicek CV, Andelfinger GU, Michaud J, Bigras JL, Richter A et al (2009) The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects. Hum Mutat 30(2):212–220PubMedCrossRef Christensen KE, Rohlicek CV, Andelfinger GU, Michaud J, Bigras JL, Richter A et al (2009) The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects. Hum Mutat 30(2):212–220PubMedCrossRef
22.
go back to reference Al Sallout RJ, Sharif FA (2010) Polymorphisms in NOS3, ACE and PAI-1 genes and risk of spontaneous recurrent miscarriage in the gaza strip. Med Princ Pract 19(2):99–104PubMedCrossRef Al Sallout RJ, Sharif FA (2010) Polymorphisms in NOS3, ACE and PAI-1 genes and risk of spontaneous recurrent miscarriage in the gaza strip. Med Princ Pract 19(2):99–104PubMedCrossRef
23.
go back to reference Goodman C, Hur J, Goodman CS, Jeyendran RS, Coulam C (2009) Are polymorphisms in the ACE and PAI-1 genes associated with recurrent spontaneous miscarriages? Am J Reprod Immunol 62(6):365–370PubMedCrossRef Goodman C, Hur J, Goodman CS, Jeyendran RS, Coulam C (2009) Are polymorphisms in the ACE and PAI-1 genes associated with recurrent spontaneous miscarriages? Am J Reprod Immunol 62(6):365–370PubMedCrossRef
24.
go back to reference Johanna GB, Michiel LB, Frits H, Cornelis K, Diederick EG (2003) The 4G5G polymorphism in the gene for PAI-1 and the circadian oscillation of plasma PAI-1. Blood 101(5):1841–1844CrossRef Johanna GB, Michiel LB, Frits H, Cornelis K, Diederick EG (2003) The 4G5G polymorphism in the gene for PAI-1 and the circadian oscillation of plasma PAI-1. Blood 101(5):1841–1844CrossRef
25.
go back to reference Eitzman DT, McCoy RD, Zheng X, Fay WP, Shen T, Ginsburg D et al (1996) Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J Clin Invest 97:232–237PubMedCrossRef Eitzman DT, McCoy RD, Zheng X, Fay WP, Shen T, Ginsburg D et al (1996) Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J Clin Invest 97:232–237PubMedCrossRef
Metadata
Title
Polymorphisms in MTHFR, MTHFD, and PAI-1 and recurrent miscarriage among North Indian women
Authors
Farah Parveen
Moni Tuteja
Suraksha Agrawal
Publication date
01-11-2013
Publisher
Springer Berlin Heidelberg
Published in
Archives of Gynecology and Obstetrics / Issue 5/2013
Print ISSN: 0932-0067
Electronic ISSN: 1432-0711
DOI
https://doi.org/10.1007/s00404-013-2877-x

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