Objective: This study aimed to detect the genotype distributions and allele frequencies of methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C and methionine synthase reductase (MTRR) A66G polymorphisms of pregnant women in Jiaodong region in China, and to investigate whether folic acid supplementation affect the pregnancy complications. Setting: A total of 7,812 pregnant women from the Jiaodong region in Shandong province in China. Methods: By using Taqman-MGB, 2,928 pregnant women (case group) were tested for the genotype distributions and allele frequencies of MTHFR C677T, A1298C and MTRR A66G polymorphisms. Folic acid metabolism ability was ranked at four levels and then pregnant women in different rank group were supplemented with different doses of folic acid. Their pregnancy complications were followed up and compared with 4,884 pregnant women without folic acid supplementation (control group) in the same hospital. Results: The allele frequencies of MTHFR C677T were 49.1 and 50.9%; those of MTHFR A1298C were 80.2 and 19.8%, and those of MTRR A66G were 74.1 and 25.9%. After supplemented with folic acid, the complication rates in different age groups were significantly reduced, especially for gestational diabetes mellitus and hypertension. Conclusion: Periconceptional folic acid supplementation and healthcare following gene polymorphism testing may be a powerful measure to decrease congenital malformations.

Keywords:
Folic acid, Methylenetetrahydrofolate reductase, Methionine synthase reductase, Polymorphism
1.
Mikolajczyk RT, Zhang J, Betran AP, Souza JP, Mori R, Gülmezoglu AM, Merialdi M: A global reference for fetal-weight and birthweight percentiles. Lancet 2011;377:1855-1861.
2.
Bakas P, Gregoriou O, Hassiakos D, Liapis A, Creatsas M, Konidaris S: Hysteroscopic resection of uterine septum and reproductive outcome in women with unexplained infertility. Gynecol Obstet Invest 2012;73:321-325.
3.
Xu L, Shi R: Noninvasive prenatal diagnosis using next-generation sequencing. Gynecol Obstet Invest 2014;77:73-77.
4.
Scholl TO, Johnson WG: Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr 2000;71:1295S-1303S.
5.
Wong S, Ordean A, Kahan M: Substance use in pregnancy. J Obstet Gynaecol Can 2011;33:367-384.
6.
Mutz-Dehbalaie I, Scheier M, Jerabek-Klestil S, Brantner C, Windbichler GH, Leitner H, Egle D, Ramoni A, Oberaigner W: Perinatal mortality and advanced maternal age. Gynecol Obstet Invest 2014;77:50-57.
7.
Kontic-Vucinic O, Sulovic N, Radunovic N: Micronutrients in women's reproductive health: I. Vitamins. Int J Fertil Womens Med 2006;51:106-115.
8.
Meka A, Reddy BM: Recurrent spontaneous abortions: an overview of genetic and non-genetic backgrounds. Int J Hum Genet 2006;6:109-117.
9.
Bogdanova N, Markoff A: Genetic predispositions to thrombophilia associated with recurrent pregnancy loss. J Reprod Med Endocrinol 2008;5:101-105.
10.
Saetre P, Grove J, Børglum AD, Mors O, Werge T, Andreassen OA, Vares M, Agartz I, Terenius L, Jönsson EG: Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and age at onset of schizophrenia: no consistent evidence for an association in the Nordic population. Am J Med Genet B Neuropsychiatr Genet 2012;159B:981-986.
11.
Shaw GM, Rozen R, Finnell RH, Todoroff K, Lammer EJ: Infant C677T mutation in MTHFR, maternal periconceptional vitamin use, and cleft lip. Am J Med Genet 1998;80:196-198.
12.
Brandalize APC, Bandinelli E, Borba JB, Felix TM, Roisenberg I, Schüler-Faccini L: Polymorphisms in genes MTHFR, MTR and MTRR are not risk factors for cleft lip/palate in South Brazil. Braz J Med Biol Res 2007;40:787-791.
13.
Scott JM, Weir DG, Molloy A, McPartlin J, Daly L, Kirke P: Folic acid metabolism and mechanisms of neural tube defects. Ciba Found Symp 1994;181:180-187; discussion 187-191.
14.
Djukic A: Folate-responsive neurologic diseases. Pediatr Neurol 2007;37:387-397.
15.
Evans SE, Mygind VL, Peddie MC, Miller JC, Houghton LA: Effect of increasing voluntary folic acid food fortification on dietary folate intakes and adequacy of reproductive-age women in New Zealand. Public Health Nutr 2014;17:1447-1453.
16.
van der Put NM, Eskes TK, Blom HJ: Is the common 677C->T mutation in the methylenetetrahydrofolate reductase gene a risk factor for neural tube defects? A meta-analysis. QJM 1997;90:111-115.
17.
Motulsky AG: Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. Am J Hum Genet 1996;58:17-20.
18.
Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, Selhub J, Rozen R: Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996;93:7-9.
19.
Mills JL, Scott JM, Kirke PN, McPartlin JM, Conley MR, Weir DG, Molloy AM, Lee YJ: Homocysteine and neural tube defects. J Nutr 1996;126:756S-760S.
20.
Kirke PN, Molloy AM, Daly LE, Burke H, Weir DG, Scott JM: Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects. Q J Med 1993;86:703-708.
21.
Chedraui P, Salazar-Pousada D, Villao A, Escobar GS, Ramirez C, Hidalgo L, Pérez-López FR, Genazzani A, Simoncini T: Polymorphisms of the methylenetetrahydrofolate reductase gene (C677T and A1298C) in nulliparous women complicated with preeclampsia. Gynecol Endocrinol 2014;30:392-396.
22.
Ranganathan P, McLeod HL: Methotrexate pharmacogenetics: the first step toward individualized therapy in rheumatoid arthritis. Arthritis Rheum 2006;54:1366-1377.
23.
Popp RA, Trifa AP, Militaru M, Crisan TO, Petrisor F, Farcas MF, Csernik FA, Pop IV: Methionine synthase reductase (MTRR) gene 66G> a polymorphism as a possible risk factor for recurrent spontaneous abortion. Analele Societatii Nationale de Biologie Celulara 2009;14:28.
24.
Chmurzynska A, Stachowiak M, Gawecki J, Pruszynska-Oszmalek E, Tubacka M: Protein and folic acid content in the maternal diet determine lipid metabolism and response to high-fat feeding in rat progeny in an age-dependent manner. Genes Nutr 2012;7:223-234.
25.
Yu G, Wang LG, Han Y, He QY: Clusterprofiler: an R package for comparing biological themes among gene clusters. OMICS 2012;16:284-287.
26.
Engelgau MM, Herman WH, Smith PJ, German RR, Aubert RE: The epidemiology of diabetes and pregnancy in the US, 1988. Diabetes Care 1995;18:1029-1033.
27.
Evers IM, De Valk HW, Visser GH: Risk of complications of pregnancy in women with type 1 diabetes: nationwide prospective study in the Netherlands. BMJ 2004;328:915.
28.
Villar J, Say L, Shennan A, Lindheimer M, Duley L, Conde-Agudelo A, Merialdi M: Methodological and technical issues related to the diagnosis, screening, prevention, and treatment of pre-eclampsia and eclampsia. Int J Gynecol Obstet 2004;85:S28-S41.
29.
Zhang J, Meikle S, Trumble A: Severe maternal morbidity associated with hypertensive disorders in pregnancy in the United States. Hypertens Pregnancy 2003;22:203-212.
30.
Wentzel P, Gäreskog M, Eriksson UJ: Folic acid supplementation diminishes diabetes- and glucose-induced dysmorphogenesis in rat embryos in vivo and in vitro. Diabetes 2005;54:546-553.
31.
van Etten RW, de Koning EJ, Verhaar MC, Gaillard CA, Rabelink TJ: Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate. Diabetologia 2002;45:1004-1010.
32.
Cechova S, Zeng Q, Billaud M, Mutchler S, Rudy CK, Straub AC, Chi L, Chan FR, Hu J, Griffiths R, et al: Loss of collectrin, an angiotensin-converting enzyme 2 homolog, uncouples endothelial nitric oxide synthase and causes hypertension and vascular dysfunction. Circulation 2013;128:1770-1780.
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2015
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