Role of intergenic interactions among folate cycle genes in the development of fetal growth retardation

Objective: Metabolic disturbances in the folate cycle in mothers can lead to fetal growth retardation (FGR). This study was to analyze the role of intergenic interactions among maternal folate cycle genes in the development of FGR. Methods: This case-control study recruited 365 women in the third trimester of pregnancy, including 122 FGR patients and 243 controls. The women were genotyped for 5 polymorphisms of the 4 folate cycle genes: MTR (rs1805087), MTRR (rs1801394), serine hydroxymethyl transferase (SHMT1; rs1979277), and TYMS (rs699517 and rs2790). The SNP × SNP interactions in the two-, three-, and four-locus models were analyzed using the multifactor dimensionality reduction method and a modification of it (the model-based multifactor dimensionality reduction method). Results: Four loci of maternal folate cycle genes (rs1805087 MTR, rs2790 TYMS, rs1801394 MTRR, and rs1979277 SHMT1) were associated with FGR in 3 significant models of single nucleotide polymorphism (SNP) × SNP interactions (two-, three-, and four-locus models) (P <0.05). The highest contribution to FGR was made by polymorphic loci rs1979277 SHMT1 (1.70% of entropy), rs1805087 MTR (0.96%), and interactions between rs1979277 SHMT1 × rs1805087 MTR (-1.11%) and rs1801394 MTRR × rs1979277 SHMT1 (−0.64%). The four-locus maternal genotype combination AG rs1801394 MTRR × AA rs1805087 MTR × CT rs1979277 SHMT1 × AG rs2790 TYMS was associated with an increased risk of FGR (β = 2.69, P = 0.012). FGR-associated SNPs were correlated with the expression of 16 genes (MTR, MTRR, SHMT1, ALKBH5, CTD-2303H24.2, ENOSF1, FAM106A, FOXO3B, LGALS9C, LLGL1, MIEF2, NOS2P2, RP11-806L2.6, SMCR8, TOP3A, and USP32P2) in various tissues and organs related to FGR pathophysiology. Conclusion: SNP × SNP interactions of maternal folate cycle genes (MTR, MTRR, SHMT1, and TYMS) are associated with the development of FGR.