Browse > Article
http://dx.doi.org/10.5653/cerm.2017.44.3.152

MTHFR 3'-untranslated region polymorphisms contribute to recurrent pregnancy loss risk and alterations in peripheral natural killer cell proportions  

Kim, Eun Sun (Department of Biomedical Science, College of Life Science, CHA University)
Kim, Jung Oh (Department of Biomedical Science, College of Life Science, CHA University)
An, Hui Jeong (Department of Biomedical Science, College of Life Science, CHA University)
Sakong, Jung Hyun (Department of Biomedical Science, College of Life Science, CHA University)
Lee, Hyun Ah (Department of Biomedical Science, College of Life Science, CHA University)
Kim, Ji Hyang (Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University School of Medicine)
Ahn, Eun Hee (Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University School of Medicine)
Kim, Young Ran (Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University School of Medicine)
Lee, Woo Sik (Fertility Center of CHA Gangnam Medical Center, CHA University)
Kim, Nam Keun (Department of Biomedical Science, College of Life Science, CHA University)
Publication Information
Clinical and Experimental Reproductive Medicine / v.44, no.3, 2017 , pp. 152-158 More about this Journal
Abstract
Objective: To identify the associations between polymorphisms of the 3'-untranslated region (UTR) of methylenetetrahydrofolate reductase (MTHFR) gene, which codes for an important regulatory enzyme primarily involved in folate metabolism, and idiopathic recurrent pregnancy loss (RPL) in Korean women. Methods: The study population comprised 369 RPL patients and 228 controls. MTHFR 2572C > A, 4869C > G, 5488C > T, and 6685T > C 3'-UTR polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis or by TaqMan allelic discrimination assays. Natural killer cell proportions were determined by flow cytometry. Results: The MTHFR 2572-5488-6685 (A-C-T) haplotype had an adjusted odds ratio of 0.420 (95% confidence interval, 0.178-0.994; p= 0.048) for RPL. Analysis of variance revealed that MTHFR 4869C > G was associated with altered $CD56^+$ natural killer cell percentages (CC, $17.91%{\pm}8.04%$; CG, $12.67%{\pm}4.64%$; p= 0.024) and folate levels (CC, $12.01{\pm}7.18mg/mL$; CG, $22.15{\pm}26.25mg/mL$; p= 0.006). Conclusion: Variants in the 3'-UTR of MTHFR are potential biomarkers for RPL. However, these results should be validated in additional studies of ethnically diverse groups of patients.
Keywords
3'Untranslated regions; Korean; Methylenetetrahydrofolate reductase; Natural killer cells; Recurrent pregnancy loss; Women;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 Wilcox AJ, Weinberg CR, O'Connor JF, Baird DD, Schlatterer JP, Canfield RE, et al. Incidence of early loss of pregnancy. N Engl J Med 1988;319:189-94.   DOI
2 Sierra S, Stephenson M. Genetics of recurrent pregnancy loss. Semin Reprod Med 2006;24:17-24.   DOI
3 Coulam CB, Clark DA, Beer AE, Kutteh WH, Silver R, Kwak J, et al. Current clinical options for diagnosis and treatment of recurrent spontaneous abortion: Clinical Guidelines Recommendation Committee for Diagnosis and Treatment of Recurrent Spontaneous Abortion. Am J Reprod Immunol 1997;38:57-74.   DOI
4 Practice Committee of American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril 2013;99:63.   DOI
5 Choi YS, Kwon H, Kim JH, Shin JE, Choi Y, Yoon TK, et al. Haplotypebased association of ACE I/D, AT1R 1166A>C, and AGT M235T polymorphisms in renin-angiotensin-aldosterone system genes in Korean women with idiopathic recurrent spontaneous abortions. Eur J Obstet Gynecol Reprod Biol 2011;158: 225-8.   DOI
6 Puri M, Kaur L, Walia GK, Mukhopadhhyay R, Sachdeva MP, Trivedi SS, et al. MTHFR C677T polymorphism, folate, vitamin B12 and homocysteine in recurrent pregnancy losses: a case control study among North Indian women. J Perinat Med 2013;41:549-54.
7 Nelen WL, Blom HJ, Steegers EA, den Heijer M, Eskes TK. Hyperhomocysteinemia and recurrent early pregnancy loss: a metaanalysis. Fertil Steril 2000;74:1196-9.   DOI
8 Ozkan Y, Yardim-Akaydin S, Erdem A, Simsek B. Variability of total thiol compounds, oxidative and nitrosative stress in uncomplicated pregnant women and nonpregnant women. Arch Gynecol Obstet 2012;285:1319-24.   DOI
9 Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, et al. Human methylenetetrahydrofolate reductase: isolation of cDNA mapping and mutation identification. Nat Genet 1994;7:551.
10 An X, Hou J, Gao T, Lei Y, Li G, Song Y, et al. Single-nucleotide polymorphisms g.151435C>T and g.173057T>C in PRLR gene regulated by bta-miR-302a are associated with litter size in goats. Theriogenology 2015;83:1477-83.e1.   DOI
11 van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, 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;62:1044-51.   DOI
12 Naushad SM, Krishnaprasad C, Devi AR. Adaptive developmental plasticity in methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism limits its frequency in South Indians. Mol Biol Rep 2014;41:3045-50.   DOI
13 Park CW, Han AR, Kwak-Kim J, Park SY, Han JY, Koong MK, et al. The role of methylenetetrahydrofolate reductase C677T polymorphism on the peripheral blood natural killer cell proportion in women with unexplained recurrent miscarriages. Clin Exp Reprod Med 2011;38:168-73.   DOI
14 Nuti F, Krausz C. Gene polymorphisms/mutations relevant to abnormal spermatogenesis. Reprod Biomed Online 2008;16:504-13.   DOI
15 Nair RR, Khanna A, Singh R, Singh K. Association of maternal and fetal MTHFR A1298C polymorphism with the risk of pregnancy loss: a study of an Indian population and a meta-analysis. Fertil Steril 2013;99:1311-8.e4.   DOI
16 Schroecksnadel K, Frick B, Wirleitner B, Schennach H, Fuchs D. Homocysteine accumulates in supernatants of stimulated human peripheral blood mononuclear cells. Clin Exp Immunol 2003;134:53-6.   DOI
17 Rai V. Methylenetetrahydrofolate reductase C677T polymorphism and recurrent pregnancy loss risk in asian population: a meta-analysis. Indian J Clin Biochem 2016;31:402-13.   DOI
18 Zhu Q, Chen Y, Dai J, Wang B, Liu M, Wang Y, et al. Methylenetetrahydrofolate reductase polymorphisms at 3'-untranslated region are associated with susceptibility to preterm birth. Transl Pediatr 2015;4:57-62.
19 Jeon YJ, Kim JW, Park HM, Kim JO, Jang HG, Oh J, et al. Genetic variants in 3'-UTRs of methylenetetrahydrofolate reductase (MTHFR) predict colorectal cancer susceptibility in Koreans. Sci Rep 2015;5:11006.   DOI
20 Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004;116:281-97.   DOI
21 Lachapelle MH, Miron P, Hemmings R, Roy DC. Endometrial T, B, and NK cells in patients with recurrent spontaneous abortion: altered profile and pregnancy outcome. J Immunol 1996;156:4027-34.
22 Hanna J, Goldman-Wohl D, Hamani Y, Avraham I, Greenfield C, Natanson-Yaron S, et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med 2006;12:1065-74.   DOI
23 Fukui A, Fujii S, Yamaguchi E, Kimura H, Sato S, Saito Y. Natural killer cell subpopulations and cytotoxicity for infertile patients undergoing in vitro fertilization. Am J Reprod Immunol 1999;41:413-22.   DOI
24 Tabiasco J, Rabot M, Aguerre-Girr M, El Costa H, Berrebi A, Parant O, et al. Human decidual NK cells: unique phenotype and functional properties--a review. Placenta 2006;27 Suppl A:S34-9.
25 Koopman LA, Kopcow HD, Rybalov B, Boyson JE, Orange JS, Schatz F, et al. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med 2003;198:1201-12.   DOI
26 Barch MJ, Knutsen T, Spurbeck JL. The AGT cytogenetics laboratory manual. 3rd ed. Philadelphia: Lippincott-Raven; 1997.
27 Rosen HR, Doherty DG, Madrigal-Estebas L, O'Farrelly C, Golden-Mason L. Pretransplantation CD56(+) innate lymphocyte populations associated with severity of hepatitis C virus recurrence. Liver Transpl 2008;14:31-40.   DOI
28 Carbone T, Nasorri F, Pennino D, Eyerich K, Foerster S, Cifaldi L, et al. D56highCD16-CD62L- NK cells accumulate in allergic contact dermatitis and contribute to the expression of allergic responses. J Immunol 2010;184:1102-10.   DOI
29 Kwak JY, Kwak FM, Ainbinder SW, Ruiz AM, Beer AE. Elevated peripheral blood natural killer cells are effectively downregulated by immunoglobulin G infusion in women with recurrent spontaneous abortions. Am J Reprod Immunol 1996;35:363-9.   DOI
30 Lee SK, Na BJ, Kim JY, Hur SE, Lee M, Gilman-Sachs A, et al. Determination of clinical cellular immune markers in women with recurrent pregnancy loss. Am J Reprod Immunol 2013;70:398-411.
31 Wu C, Gong Y, Sun A, Zhang Y, Zhang C, Zhang W, et al. The human MTHFR rs4846049 polymorphism increases coronary heart disease risk through modifying miRNA binding. Nutr Metab Cardiovasc Dis 2013;23:693-8.   DOI