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

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%±8.04%; CG, 12.67%±4.64%; p=0.024) and folate levels (CC, 12.01±7.18 mg/mL; CG, 22.15±26.25 mg/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.

Figure 1. The MTHFR 4869C>G polymorphism is associated with differences in CD56⁺ NK cell percentages and folate levels in women with recurrent pregnancy loss. Statistical analyses were performed using the Kruskal-Wallis test for the MTHFR 4869C>G genotype and the percentages of CD56⁺ NK cells (A) and folate levels (B) in women with three or more lost pregnancies. NK, natural killer; MTHFR, methylenetetrahydrofolate reductase. ^a)p<0.05.