3'UTR SNPs and Haplotypes in the GATA4 Gene Contribute to the Genetic Risk of Congenital Heart Disease.
OBJECTIVE
Single-nucleotide polymorphisms within a microRNA binding site can have different effects on gene expression, influencing the risk of disease. This study aimed to evaluate the association between single-nucleotide polymorphisms and haplotypes in the 3'UTR of the GATA4 gene and congenital heart disease risk.


METHODS
Bioinformatics algorithms were used to analyze single-nucleotide polymorphisms in putative microRNA-binding sites of GATA4 3'UTR and to calculate the difference in free energy of hybridization (ΔFE, kcal/mol) for each wild-type vs the variant allele.


RESULTS
The study population comprised 146 Caucasian patients (73 males; 6.68 ± 7.79 years) and a 265 healthy newborn participants (147 males). The sum of all |ΔFE| was considered to predict the biological importance of single-nucleotide polymorphisms binding more microRNAs. Next, the 4 polymorphisms (+1158C > T, +1256 A > T, +1355 G > A, +1521C > G) with the highest predicted |ΔFEtot| (9.91, 14.85, 11.03, 21.66kcal/mol, respectively) were genotyped in a case-control study (146 patients and 250 controls). Applying a correction for multiple testing only the +1158 T allele was found to be associated with a reduced risk showing significant difference between patients and controls. Haplotype analysis showed that the T-T-G-C haplotype (more uncommon in congenital heart diseases than in controls) was associated with a significantly decreased risk (P = .03), while the rare C-A-A-C haplotype, which was very uncommon in controls (0.3%) compared with the disease (2.4%), was associated with a 4-fold increased risk of disease (P = .04).


CONCLUSIONS
Common variants in 3'UTR of the GATA4 gene jointly interact, affecting the congenital heart disease susceptibility, probably by altering microRNA posttranscriptional regulation.
Consiglio Nazionale delle Ricerche, Institute of Clinical Physiology, Pisa, Italy.
Silvia
S
Pulignani
Consiglio Nazionale delle Ricerche, Institute of Clinical Physiology, Pisa, Italy. Electronic address: vecoli@ifc.cnr.it.
Cecilia
C
Vecoli
Consiglio Nazionale delle Ricerche, Institute of Clinical Physiology, Pisa, Italy.
Saverio
S
Sabina
Consiglio Nazionale delle Ricerche, Institute of Clinical Physiology, Pisa, Italy.
Ilenia
I
Foffa
Consiglio Nazionale delle Ricerche, Institute of Clinical Physiology, Pisa, Italy.
Lamia
L
Ait-Ali
Consiglio Nazionale delle Ricerche, Institute of Clinical Physiology, Pisa, Italy.
Maria Grazia
MG
Andreassi
D020413:3' Untranslated Regions / Q000235:genetics*; D000483:Alleles; D001665:Binding Sites; D002648:Child; D002675:Child, Preschool; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D020413:3' Untranslated Regions; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human
3’UTR; Cardiopatía congénita; Congenital heart disease; GATA4; Haplotipo; Haplotype; Polimorfismos de nucleótido único; Single nucleotide polymorphisms