Balkan Journal of Medical Genetics

ASSOCIATION OF NFKB1, NKX2-5, GATA4 AND RANKL GENE POLYMORPHISMS WITH SPORADIC CONGENITAL HEART DISEASE IN GREEK PATIENTS
Aidinidou L1, Chatzikyriakidou A1, Giannopoulos A2, Karpa V1, Tzimou I2, Aidinidou E3, Fidani L1,*
*Corresponding Author: Professor Liana Fidani, Department of General Biology, Medical School, Aristotle University of Thessaloniki, University Campus, GR-54124, Thessaloniki, Greece. Tel.: +30- 231-099-9165. Fax: +30-231-099-9019. E-mail: sfidani@auth.gr
page: 15

INTRODUCTION

Congenital heart disease (CHD), is a structural defect of the heart and the great vessels, and is an important cause of mortality in newborn infants, with an estimated prevalence rate of 1.0% in live births [1,2]. As a multifactorial disease, both genetics and environmental factors contribute to its development and approximately 30.0% of CHD present as part of a genetic syndrome or chromosomal abnormality [3]. Multiple environmental factors, such as viral infections with rubella, febrile illness and influenza can affect the fetal development and increase the incidence of CHD. Other implicated maternal factors include diabetes, systemic lupus erythematosus, exposure to therapeutic drugs, alcohol consumption and cigarette smoking [1,4]. Nonetheless, to date, the molecular mechanisms that lead to the occurrence of CHD are largely unknown. Up to the present, more than 40 genes encoding transcription factors, signal transduction and structural proteins, have been revealed to be involved in congenital heart defects. Any mutation in these genes may lead to abnormal heart structure and CHD [5,6]. The NKX2-5 and GATA4 genes have been associated with CHD discovered by linkage analysis and candidate gene studies in highly affected families [6]. The NKX2-5 is a member of the NKX2 family located on chromosome 5134 and consists of two exons that encode a 324-amino acid transcription factor. The genetic polymorphism rs2277923 is a synonymous mutation 63A>G leading to an amino acid substitution of glutamine by glutamine at position 21 (Glu21Glu) and was reported as a genetic predictor of CHD [7]. In ad- dition, GATA4 interacts with NKX2-5, and it is known that mutations in transcription factors can result in severe cardiac defects [3]. For these reasons, the GATA4 gene polymorphism, an important transcription factor that is involved in the morphogenesis of the heart, was chosen to be studied in order to further validate its pivotal role in modulating CHD risk. Transcription factor GATA4 is a 442-amino acid protein, which is mapped to chromosome 8q22-23 [6]. Consistent with these findings, a common variant +1158C>T (rs11785481) in the 3’ untranslated region (3’UTR) of the GATA4 gene, was confirmed to be associated with CHD susceptibility, possibly by altering microRNA (miRNA) posttranscriptional regulation [8]. Another transcription factor implicated in the pathogenesis of CHD is the NF-κB1 (nuclear factor-κ B1) gene. The NF-κB gene is a member of transcription factors that regulate numerous biological processes such as inflammation, proliferation and cell survival. The NF-κB family has five subunits: p65(RelA), RelB(RelB), c-Rel(Rel), p50/p105 (NFKB1) and p52/p100 (NFKB2) [9]. The human NFKB1 gene is located on chromosome 4q24 and encodes a 50 kDa DNA-binding peptide (p50). Interestingly, a common –94ins/delATTG variant (rs28362491) that is located on the promoter of the NFKB1 gene, was identified as a potential risk factor for CHD in a Chinese population [9]. A RANKL gene variant was also chosen to be investigated as it has been found that down-regulation of RANKL may inhibit the NF-κB signaling pathway and lead to a congenital heart anomaly [10]. Receptor activator of the NF-κB ligand (RANKL) interacts with RANK and active NF-κB transcription factor [11]. In line with NFKB1, the genetic variant (rs4531631) in RANKL might be a significant predisposing factor of CHD [10]. Receptor activator of the NF-κB ligand (RANKL), is a 314-amino acid transmembrane protein, encoded by the gene RANK, which is located on chromosome 13q14.11. The RANKL gene belongs to the TNF cytokine family [12] and expressed by osteoblasts, fibroblasts, and activated T and B cells. Also, RANKL and RANK also had a combined role on target cells to regulate cell differentiation, activation and apoptosis [13]. Taking these considerations into account, the purpose of the present study was to examine the potential role of these variants in the development of CHD, for the first time, among the Greek population.

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