ASSOCIATION BETWEEN SERUM HOMOCYSTEINE LEVELS AND METHYLENETETRAHYDROFOLATE REDUCTASE C677T AND A1298C GENE POLYMORPHISMS IN WOMEN WITH RECURRENT MISCARRIAGE

Irena Kostovska; Svetlana Cekovska; Katerina Tosheska Trajkovska; Danica Labudovic; Julijana Brezovska Kavrakova; Sonja Topuzovska; Olivija Efinska Mladenovska; Meri Kirjas

Irena Kostovska 1Institute of Medical and Experimental Biochemistry, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
Svetlana Cekovska Institute of Medical and Experimental Biochemistry, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
Katerina Tosheska Trajkovska Institute of Medical and Experimental Biochemistry, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
Danica Labudovic Institute of Medical and Experimental Biochemistry, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
Julijana Brezovska Kavrakova Institute of Medical and Experimental Biochemistry, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
Sonja Topuzovska Institute of Medical and Experimental Biochemistry, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
Olivija Efinska Mladenovska Institute of Immunobiology and Human Genetics, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
Meri Kirjas Institute of Immunobiology and Human Genetics, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia

Abstract

Recurrent miscarriage (RM) has been linked to hyperhomocysteinemia and the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C gene mutations. The study aimed to investigate the association between serum homocysteine levels and methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms in women with idiopathic recurrent miscarriage. In this study, we included 30 women with idiopathic recurrent miscarriage and 28 healthy pregnant women as the control group. After genotyping, all women were divided into three groups: Control group (N = 28) (no more than one mutation in both loci of the MTHFR gene, C667T and A1298C), second group (N = 13), homozygous (both copies of either the C677T mutation or the A1298C mutation), and third group (N = 17) compound heterozygous (having one copy of the A1298C mutation and one copy of the C677T mutation). Genotyping was performed by reversal hybridization with a CVD strip assay manufactured by Vienna Lab, Austria. A chemiluminescent immunoenzyme assay was used to determine the concentrations of homocysteine in the serum. In the control group, we found that 18% of women have elevated homocysteine levels (>15 mol/L); in the second group, 23% of women have hyperhomocysteinemia; and in the third group, 35% of women have elevated homocysteine levels. Despite the high percentage of subjects with hyperhomocysteinemia in compound heterozygous, no significant differences were observed in serum homocysteine levels between the studied groups (p > 0.05). Serum homocysteine levels and methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms are not associated with idiopathic recurrent miscarriage.

Keywords: homocysteine, methylenetetrahydrofolate reductase, recurrent miscarriage, genotyping.

References

1. Hodes-Wertz B, Grifo J, Ghadir S, Kaplan B, Laskin CA, Glassner M, MunnÃ© S. Idiopathic recurrent miscarriage is caused mainly by aneuploid embryos. Fertil Steril 2012;98(3): 675-680.
2. Imam SN, Shamsi MB, Kumar K, Deka D, Dada R. Idiopathic recurrent pregnancy loss: role of paternal factors; a pilot study. J Reprod Infertil 2011;12(4): 267-276.
3. Dell'edera D, L'episcopia A, Simone F, Lupo M, Epifania A, Allegretti A. Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms and susceptibility to recurrent pregnancy loss. Biomed Rep 2018;8(2): 172-175.
4. Xu Y, Ban Y, Ran L, Yu Y, Zhai S, Sun Z, et al. Relationship between unexplained recurrent pregnancy loss and 5,10-methylenetetrahydrofolate reductase) polymorphisms. Fertil Steril 2019;111(3): 597-603.
5. Brandt NB, Kristensen MLS, Catalini L, Fedder J. Effect of paternal health on pregnancy loss-A review of current evidence. Andrologia 2022;54(1): e14259.
6. Undas A, Chojnowski K, Kluskowska A, ÅÄ™towska M, Mital A, MÅ‚ynarski W, et al. Determine nation and interpretation of MTHFR gene mutations in gynecology and in ternal medicine. Pol Arch Intern Med 2019;129: 728-732.
7. Zammiti W, Mtiraoui N, Mahjoub T. Lack of consistent association between endothelial nitric oxide synthase gene polymorphisms, homocysteine levels and recurrent pregnancy loss in Tunisian women. Am J Reprod Immunol 2008;59(2): 139â€“145.
8. Creus M, Deulofeu R, PeÃ±arrubia J, Carmona F, Balasch J. Plasma homocysteine and vitamin B12 serum levels, red blood cell folate concentrations, C677T methylenetetrahydrofolate reductase gene mutation and risk of recurrent miscarriage: a case-control study in Spain. CCLM 2013;51(3): 693â€“699.
9. Juan L, Danqin F, Shiwei H, Qichang W, Zhiying S, Huiming Y. Meta-analysis: association of homocysteine with recurrent spontaneous abortion. Women Health 2021;61(7): 713-720.
10. Mukhopadhyay I, Pruthviraj V, Rao PS, Biswas M. Hyperhomocysteinemia in recurrent pregnancy loss and the effect of folic acid and vitamin B12 on homocysteine levels: a prospective analysis. Int J Reprod Contracept Obstet Gynecol 2017;6(6): 2258-2261.
11. Ehab AME, Majed SA, Mohamed YA, Ozaz YMA, Mahmoud AS, Abdullah IA, et al. Association Between Hyperhomocysteinemia and Recurrent Miscarriages: A Cross-Sectional Study Set in Saudi Arabia. Bahrain Med Bull 2022;44 (3): 1036-1040.