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

TL;DR

This study finds that genetic variations in the HIF-1α gene are linked to an increased risk of severe pregnancy-related high blood pressure disorders.

Contribution

The study identifies specific HIF-1α gene polymorphisms and haplotypes associated with severe hypertensive disorders of pregnancy in triads.

Findings

Double-dose T allele in rs4902080 increases risk of severe hypertensive disorders in mothers and children.

Heterozygous CT genotype for rs2057482 and rs11549465 is protective against these disorders in both mothers and children.

The C-c-c-G haplotype reduces risk compared to the C-T-T-G haplotype in mothers and children.

Abstract

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.

The online version contains supplementary material available at 10.1007/s43032-025-01835-5.