Studying the role of interlocus interactions of folate cycle genes and matrix metalloproteinases in the formation of fetal growth retardation

Abstract

Background: Fetal growth retardation (FGR) is one of the most common pregnancy complications that can adversely affect the shortand long-term health of newborns. The search for maternal polymorphisms of candidate genes involved in the formation of FGR is important. The aim of the study: To study the role of interlocus interactions of the folate cycle genes and matrix metalloproteinases in the formation of fetal growth retardation. Materials and methods: 477 pregnant women were examined (234 women whose pregnancy was complicated by intrauterine growth retardation and 243 women who had a physiological course of pregnancy (control group)). SNP×SNP interactions of 10 polymorphic loci of matrix metalloproteinase genes and genes affecting the folate cycle associated with the development of FGR were studied using the dimensionality reduction method (MDR method modified by MB-MDR). Validation of the results was carried out using a permutation test (1000 permutations were performed). FGR-related polymorphisms were analyzed in silico for their functional significance. To determine the biological pathways, the following programs were used: Gene Ontology and Genomania. Results: The 7 most significant models of SNP×SNP interactions of matrix metalloproteinase genes and folate cycle genes associated with the development of FGR have been established, which include eight of the 10 SNPs under consideration: rs1805087 MTR, rs1801394 MTRR, rs1979277 SHMT1, rs1799750 MMP-1, rs243865 MMP-2, rs3025058 MMP-3, rs11568819 MMP-7, rs17577 MMP-9 (рperm≤0,05). The largest number of models includes polymorphic loci rs1979277 (7 models), rs243865 (4 models), rs3025058 (3 models). The two-locus combination of TT rs243865 MMP2 x TT rs1979277 SHMT1 genotypes (beta = -0,68, p=0,001) has the most significant association with FGR. These polymorphisms exhibit pronounced functional effects in relation to 38 genes that are involved in the biological pathways of collagen metabolism (mainly in its catabolic breakdown) and modulation of the activity of matrix metalloproteinases (mainly in the processes of increasing the activity of matrix metalloproteinases, causing the breakdown of the extracellular matrix). Conclusion: Interlocus interactions of folate cycle genes and matrix metalloproteinases determine susceptibility to fetal growth retardation.