Projects / Programmes
ANALYSIS OF FOLATE METABOLISM BIOMARKERS IN THE RISK ASSESSMENT FOR NEURAL TUBE DEFECTS
| Code |
Science |
Field |
Subfield |
| 3.05.00 |
Medical sciences |
Human reproduction |
|
| Code |
Science |
Field |
| B570 |
Biomedical sciences |
Obstetrics, gynaecology, andrology, reproduction, sexuality |
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
birth defects, folic acid, folic acid metabolism, cell lines, DNA methylation, microRNA
Researchers (18)
Organisations (2)
Abstract
The aim of the proposal is to translate contemporary research approaches and concepts including genomic, metabolomic and transcriptomi technologies into clinical practice.
Birth defects represent a significant public health concern, since they impact survival and life quality of affected children and their parents. Among the most common congenital abnormalities are defects associated with folate metabolism, which include neural tube defects, congenital heart defects, and orofacial clefts. Despite intensive epidemiological, clinical and experimental research the aetiology of the congenital abnormalities remains unresolved. One of the known risk factors is insufficient folic acid intake prior and during the pregnancy. However folic acid supplementation can only partially prevent these anomalies. Therefore, we assume that there are other important elements including mechanisms involved in folate metabolism, genetic and epigenetic factors.
Obectives
OBJECTIVE 1: Impact of methylated and non-methylated forms of folic acid supplementation on folate status and identification of genes that affect the level of the folate metabolites and methionine in the blood of healthy subjects
The efficacy of methylated and unmethylated forms of folic acid on folate and homocysteine levels in the blood of healthy subjects will be compared. The expression level of the entire genome will be studied to identify genes, whose products are responsible for regulating levels of folate and homocysteine in the organism. Usefulness of identified genes in clinical practice will be verified in a confirmatory study on other populations by genotyping selected polymorphisms in these genes.
OBJECTIVE 2: Examination of genotypic and environmental influences on concentrations of selected metabolites of folate and methionine cycle in cell lines
In vitro model of lymphoblastoid cell lines will allow us to study metabolic and genetic factors that influence the levels of folate and homocysteine in the cell, and thus the methylation of DNA and expression of miRNA, in a controlled way. We will examine how cells with different genotypes for the genes that encode enzymes of folate and methionine cycle, respond to treatment with various folate and methionine metabolites.
OBJECTIVE 3: Development of the risk prediction algorithm for the NTD and other birth defect associated with folic acid metabolism, based on a retrospective comparison of the genetic characteristics of pairs of mothers and children with and without the birth defects
The maximum number of foetal and maternal risk factors (genetic, demographic and food intake information) will be identified in the groups of the children with and without birth defect, and their mothers. All mothers and children will be genotyped; mothers will be asked to complete the survey about demographic characteristics and dietary intake. In the next stage, by comparing the genetic, demographic and food intake information, we will develop the risk prediction algorithm for the NTD and other birth defect associated with folic acid metabolism for optimal folate intake and monitoring of pregnancy.
Relevance
The project will be conducted by an international, interdisciplinary team including partners from University Medical Center Ljubljana (dr. Ksenija Gersak), University of Ljubljana, Faculty of Pharmacy (dr. Irena Mlianric-Rascan), Estonian Genome Project and Institute for molecular and cell biology, University of Tartu (dr. Andres Metspalu), and Sackler Faculty of Medicine, University of Tel Aviv (dr. David Gurwitz). Translation of genomic, transcriptomic and metabolomic methodologies shall improve both diagnosis and prevention of congenital developmental anomalies. All of this indicates a high scientific and socio-economic relevance. Proposed approach and expertise of the group shall assure high-scientific relevance and accomplishments of project’s ambitious goals.
Significance for science
Perinatal mortality rates are an indicator of the health status of a given population and reflect country’s economic development and standard of living. Congenital developmental anomalies represent a leading cause of death of children in their first year of life. Among them, those associated with folate metabolism (congenital heart defects, neural tube defects and orofacial clefts) are the most common. Studies indicate that aforementioned disorders occur more frequently in lower socioeconomic strata. Heart defects and neural tube defects strongly influence the survival of neonates whereas orofacial clefts primarily affect the quality of the children life. At the same time, we know, that in Slovenia only 19 % of pregnant women are taking folic acid properly. Identification of potential genetic biomarkers associated with decreased folate status allows prediction of the birth defects associated with folate metabolism. Consequently, this could lead to the reduction of incidence of birth defects and improvement of pregnancy outcomes.
Significance for the country
Proposed project was interdisciplinary and was based on collaboration of Faculty of Pharmacy, and University Medical Centre Ljubljana. All the mentioned aspects positively affect the scientific work in their home institution; also equipment, materials and research funds will be better exploited. An important part of the project is also training and development of young researchers; in March 2017 one of them (research fellow) will start to work on a doctoral thesis in the field of pharmacogenomics of folate cycle, which follows directly from the results of this project.
Most important scientific results
Annual report
2013,
2014,
2015,
final report
Most important socioeconomically and culturally relevant results
Annual report
2013,
2014,
2015,
final report
