Genetic predisposition to the development of congenital heart diseases: Role of xenobiotic biotransformation genes.

Congenital heart diseases are one of the most common multi-factorial fetal abnormalities caused by a complex of endo- and exogenous factors. It is known that mutations in xenobiotic biotransformation genes can be associated with the pathogenesis of congenital heart diseases. In the presented research, 131 children with congenital heart diseases and 101 women having children with this pathology were included in the study group. In control group, 103 healthy children and their mothers were included. Single-nucleotide polymorphisms in the xenobiotic biotransformation genes CYP1A1 (rs1048943), CYP1A2 (rs762551), GSTP1 (rs6591256, rs1871042 and rs17593068) were detected by the real-time polymerase chain reaction. Gene-gene interactions were determined using the Multifactor Dimensionality Reduction method. We obtained no difference in the frequency of CYP1A1, CYP1A2 and GSTP1 between the study and control groups. At the same time, the genetic combinations GSTP1 (rs6591256)-GSTP1 (rs1871042) and GSTP1 (rs6591256)-GSTP1 (rs1871042)-CYP1A1 (rs1048943) in women; and GSTP1 (rs1793068)-GSTP1 (rs6591256)-GSTP1 (rs1871042)-CYP1A1 (rs1048943)-CYP1A2 (rs762551) in children contribute to the pathogenesis of congenital heart diseases.

Polymorphisms in folate-metabolizing genes and risk of having an offspring with congenital anomalies in the West Siberian region of Russia: a case-control study.

OBJECTIVE: Periconceptional folate supplementation prevents a number of congenital anomalies (CA). The aim of our study was to investigate the association of 11 polymorphisms in the folate-metabolizing genes with the risk of having an offspring with CA in the Russian ethnic group. METHOD: We genotyped 280 mothers having a CA-affected pregnancy and 390 control mothers. The most common malformations among the cases were CA of the nervous, urinary, and cardiovascular systems, and these groups were analyzed separately. RESULTS: In the whole group of CA, we revealed the associations of MTHFR C677T and MTR A2756G loci with increased risk of CA-affected pregnancy. In the group of CA of the cardiovascular system, we observed an association of MTHFR A1298C with decreased risk and an association of MTR A2756G with increased risk of CA. After the Bonferroni correction, only the association between the genotype MTR 2756GG and the risk of having a fetus with CA of the cardiovascular system remained statistically significant (OR = 4.99, P = 0.03). CONCLUSION: These findings indicate that locus A2756G in the MTR gene may play a role in susceptibility to CA of the cardiovascular system in West Siberia, but further research is necessary to confirm the association.

Mechanisms of HLA DR Gene Selection in Early Ontogenesis.

Hypothesis explaining the cause of MHC gene frequency variation in two consecutive generations is presented. The four stages of MHC genes selection is postulated: gamete processing, reaction of fertilization, preimplatation and implatation embryos survival, postnatal selection. On the stage of gametogenesys different adaptivity of germ cells is connected with MHC alleles. On the stage of fertilization and implantation the main factor of selection is cell-to-cell polar interaction with the participation of MHC: spermatozoa and ovum; cleavaging cells of early embryo; cells of early embryo and endometrium. On the stage of development of implantation embryo the essential role play MHC-restricted immune mother-fetus interactions. Postnatal selection is connected with more or less resistance of children and adults to MHC-associated diseases.

Genetic Aspects of Immunopathology in Prenatal and Postnatal Period.

The development of immunopathology in prenatal and postnatal periods has been studied with special refer to immune interaction character in mother-fetus system and inherited HLA DR genes. The immune variant of customary recurrent abortion has been shown to be associated with the HLA DR2 and HLA DR6 genes, with poor immune recognition of fetus HLA antigens and absence of serum suppressive factors in women. The distorted immune interactions with HLA antigens in the mother-fetus system are transformed into the neonatal period as purulent-septic diseases and hemolytic disease of the newborns. The development of immunopathology, the maturation of main immunity parameters and postvaccinal immune response in the first-year-infants are associated with the inherited HLA DR genes.

Effect of Immune Interactions in Mother-Fetus System on Formation of Immune Response to Main Vaccinal Antigens.

Immune disturbances in the mother-fetus system are transformed to the postnatal period in the form of different kinds of immune pathology. Do these disturbances have an effect on the formation of postvaccinal immune response? A study was made in 81 children who were 14 months old. The immune response to diphtheria and measles antigen in those children was studied in the passive hemagglutination reaction. In order to detect immune disturbances in the mother-fetus system, their parents were tested using the methods: a mixed culture of lymphocytes (MLC) of the parents and determination of the blocking activity of the female serum (BAS) in MLC. The conducted study showed that there is a mutual relationship between the weak proliferative response in the MLC of the parents, combined with the absence of BAS, and low immune response to the diphtheria antigen. As regards measles vaccination, a close relationship between the strength of the immune response and immune reproductive disturbances has not been established. The obtained data may be used to predict the efficacy of alum precipitated DTP and DT vaccines.