Association of maternal hypertension and diabetes with variants of the NKX2-5, LEFTY1 and LEFTY2 genes in children with congenital heart defects: a case-control study from Pakistani Population.

Background: Globally, congenital heart defect (CHD) is the most common congenital malformation, responsible for higher morbidity and mortality in the pediatric population. It is a complex multifactorial disease influenced by gene-environment and gene-gene interactions. The current study was the first attempt to study these polymorphisms in common clinical phenotypes of CHD in Pakistan and the association between maternal hypertension and diabetes with single nucleotide polymorphisms (SNPs) in children.

Methods: A total of 376 subjects were recruited in this current case-control study. Six variants from three genes were analyzed by cost-effective multiplex PCR and genotyped by minisequencing. Statistical analysis was done by GraphPad prism and Haploview. The association of SNPs and CHD was determined using logistic regression.

Results: The risk allele frequency was higher in cases as compared to healthy subjects, but the results were not significant for rs703752. However, stratification analysis suggested that rs703752 was significantly associated with the tetralogy of Fallot. The rs2295418 was significantly associated with maternal hypertension (OR = 16.41, p = 0.003), while a weak association was present between maternal diabetes and rs360057 (p = 0.08).

Conclusion: In conclusion, variants in transcriptional and signaling genes were associated with Pakistani pediatric CHD patients that showed varied susceptibility between different clinical phenotypes of CHD. In addition, this study was the first report regarding the significant association between maternal hypertension and the LEFTY2 gene variant.