Interactions between genetic variants involved in the folate metabolic pathway and serum lipid, homocysteine levels on the risk of recurrent spontaneous abortion

Abstract

Background: The interaction between folate pathway gene polymorphisms and homocysteine, serum lipid leverls are poorly understood in patients with recurrent spontaneous abortion (RSA). The aim of this study is to explore the effects of folate pathway gene polymorphisms (the 5-10-methylenetetrahydrofolate reductase, MTHTR C677T, MTHFR A1298C and the methionine synthase reductase, MTRR A66G) and their interactions with homocysteine on serum lipid levels in patients with RSA.

Methods: A total of 403 RSA women and 342 healthy women were randomly selected. Genotyping of the MTHFR C677T, A1298C and MTRR A66G were performed by TaqMan-MGB technique. Serum homocysteine, folate, fasting glucose, fasting insulin, Interleukin 6, Tumor necrosis factorα (TNFα) and lipid profiles were measured according to the kits. Continuous variables were analyzed using 2-sample t-tests. Categorical variables were analyzed and compared by χ² or Fisher's exact tests. Unconditional logistic regression model was applied to test the interactions of gene polymorphisms on RSA.

Results: The distribution of genotype of CC, CT TT and T allele of MTHFR C677T, genotype of AA and C allele of MTHFR A1298C, and genotype of AA, AG and G allele of MTRR A66G were different between cases and controls (all p were < 0.05). There were significant interactions between MTHFR C677T-A1298C and MTHFR A1298C-MTRR A66G in RSA group and control group, with ORs of 1.62 (95%CI: 1.28-2.04, p < 0.001) and 1.55 (95%CI: 1.27-1.88, p < 0.001), respectively. Serum TNFα level and insulin resistant status (HOMR-IR) were higher in RSA group than in control group (p = 0.038, 0.001, respectively). All the three gene SNPs except MTRR 66AG gene variant had detrimental effects on HOMA-IR (all p were < 0.05). RSA group who carried the MTHFR 677CT, TT, CT/TT genotypes and MTRR 66AG, AG/GG genotypes had detrimental effects on serum homocysteine levels, the MTHFR 677CT, CT/TT genotype carriers had favorable effects on serum folate levels, the MTHFR 677TT, CT/TT, 1298 AC, AC/CC genotype carriers had detrimental effects on serum low-density lipoprotein cholesterol (LDL-C) levels, and the MTRR 66AG genotype carriers had lower high-density lipoprotein cholesterol (HDL-C) levels than the AA genotype carriers (all p were < 0.05).

Conclusions: Interaction between the MTHFR C677T, A1298C and MTHFR A1298C, MTRR A66G are observed in our RSA group. Besides, all the three gene SNPs except MTRR 66AG gene variant had detrimental effects on HOMA-IR. MTHFR C677T and MTRR A66G gene variants had detrimental effects on serum homocysteine levels and insulin resistance status, while MTHFR C677T, A1298C and MTRR A66G gene variants had detrimental effects on certain serum lipid profiles.

Keywords: Homocysteine; Lipid profiles; MTHFR A1298C; MTHFR C677T; MTRR A66G; Recurrent spontaneous abortion.