Hypoxia-Inducible Factor 1-Alpha Gene Polymorphisms Impact Risk of Severespectrum Hypertensive Disorders of Pregnancy: A Case-Control Study

Hypoxia-inducible factor 1-alpha (HIF-1α) regulates cellular responses to hypoxia. Overexpression of HIF-1α is associated with abnormal placental trophoblast invasion and hypertensive disorders of pregnancy. We evaluated the putative association between polymorphisms and haplotypes in parental and child HIF-1α genes and the risk of severe-spectrum hypertensive disorders of pregnancy. Case (N = 179) and control (N = 34) mother-father-child triads were recruited by an internet-based method. Cases were defined as HELLP (Hemolysis, Elevated Liver enzymes and Low Platelets) syndrome or pre-eclampsia with severe features. Four HIF-1α single nucleotide polymorphisms were genotyped: rs4902080, rs2057492, rs11549465, rs10144958. Relative risks and 95% confidence intervals were estimated using log-linear free response models, adjusting for correlation between familial genotypes. Relative risk of severe-spectrum hypertensive disorder of pregnancy was increased with double-dose carriage of the T allele for SNP rs4902080 in both mother [RR 6.96, p = 0.028] and child [RR 5.77, p = 0.031]. Child double-dose of the T allele for SNP rs10144958 [RR 5.52, p = 0.047] also increased risk. The heterozygous genotype (CT) for SNPs rs2057482 and rs11549465 was protective against hypertensive disorders of pregnancy when carried by mother [rs2057482: RR 0.34, p < 0.001; rs11549465: RR 0.23, p < 0.001] or child [rs2057482: RR 0.44, p < 0.001; rs11549465: RR 0.31, p < 0.001]. A single copy of the C-c-c-G haplotype (rs4902080-rs2057482-rs11549465-rs10144958, N = 147), conferred decreased risk versus the C-T-T-G haplotype in mother [RR 0.28, p < 0.001] and child [RR 0.36, p < 0.001]. No parent-of-origin effects were seen. We conclude that polymorphism changes and haplotypes in the HIF-1α gene of mothers, fathers, and children are associated with risk for severe-spectrum hypertensive disorders of pregnancy.