Baldauf Claire, Wei Chen, Pickering Trevor A, Grubbs Brendan, Gjessing Håkon, Wilson Melissa L
Keck School of Medicine, Department of Pediatrics, University of Southern California, Los Angeles, CA, USA.
Children's Hospital Los Angeles, Los Angeles, CA, USA.
Reprod Sci. 2025 Apr;32(4):993-1002. doi: 10.1007/s43032-025-01835-5. Epub 2025 Mar 14.
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.
缺氧诱导因子1α（HIF-1α）调节细胞对缺氧的反应。HIF-1α的过表达与胎盘滋养层细胞异常侵袭及妊娠高血压疾病有关。我们评估了父母及子代HIF-1α基因多态性和单倍型与严重型妊娠高血压疾病风险之间的假定关联。通过基于互联网的方法招募了病例组（N = 179）和对照组（N = 34）的母婴三联体。病例定义为HELLP（溶血、肝酶升高和血小板减少）综合征或伴有严重特征的先兆子痫。对四个HIF-1α单核苷酸多态性进行基因分型：rs4902080、rs2057492、rs11549465、rs10144958。使用对数线性自由反应模型估计相对风险和95%置信区间，并对家族基因型之间的相关性进行校正。母亲和孩子中，SNP rs4902080的T等位基因双剂量携带均增加了严重型妊娠高血压疾病的相对风险[母亲：RR 6.96，p = 0.028；孩子：RR 5.77，p = 0.031]。SNP rs10144958孩子的T等位基因双剂量携带[RR 5.52，p = 0.047]也增加了风险。当母亲[rs2057482：RR 0.34，p < 0.001；rs11549465：RR 0.23，p < 0.001]或孩子[rs2057482：RR 0.44，p < 0.001；rs11549465：RR 0.31，p < 0.001]携带SNP rs2057482和rs11549465的杂合基因型（CT）时，对妊娠高血压疾病具有保护作用。单拷贝的C-c-c-G单倍型（rs4902080-rs2057482-rs11549465-rs10144958，N = 147）与母亲[RR 0.28，p < 0.001]和孩子[RR 0.36，p < 0.001]中的C-T-T-G单倍型相比，风险降低。未观察到亲本来源效应。我们得出结论，母亲、父亲和孩子的HIF-1α基因多态性变化和单倍型与严重型妊娠高血压疾病风险相关。
