Microsatellite polymorphism in the heme oxygenase-1 promoter is associated with nonsevere and late-onset preeclampsia.

Preeclampsia is a serious and phenotypically heterogeneous vascular pregnancy disorder. Heme oxygenase-1 (HO-1) is a stress response enzyme that may protect the maternal endothelium and facilitate adequate metabolic adaptation to pregnancy by its antioxidant and anti-inflammatory functions. HO-1 stress response is modulated by HO-1 gene (HMOX1) polymorphisms. Individuals with the long allele of a guanine-thymine (GTn) microsatellite repeat located in the promoter region of HMOX1 have a higher risk of cardiometabolic diseases compared with those with the short allele. We investigated whether the long GTn allele of HMOX1 is associated with subtypes of preeclampsia. The GTn repeat was genotyped in 759 patients and in 779 controls from the Finnish Genetics of Preeclampsia Consortium (FINNPEC) cohort using DNA fragment analysis. In subtype analyses, the long-long (LL) genotype was associated with nonsevere (additive model: odds ratio [OR], 1.94; 95% confidence interval [CI], 1.13-3.31; recessive model: OR, 1.39; 95% CI, 1.02-1.89) and late-onset (additive model: OR, 1.44; 95% CI, 1.02-2.05; recessive model: OR, 1.28; 95% CI, 1.02-1.59) preeclampsia and with preeclampsia without a small-for-gestational-age infant (recessive model: OR, 1.27; 95% CI, 1.02-1.58). The long allele was associated with nonsevere (OR, 1.35; 95% CI, 1.07-1.70) and late-onset (OR, 1.21; 95% CI, 1.03-1.42) preeclampsia and with preeclampsia without a small-for-gestational-age infant (OR, 1.19; 95% CI, 1.02-1.40). Moreover, both the LL genotype and the long allele were associated with preeclampsia in women who had smoked during pregnancy. In conclusion, the GTn long allele seems to predispose to late-onset, less severe form of preeclampsia. This finding supports the role of HO-1 in the pathogenesis of preeclampsia and suggests that the HO-1 pathway may provide a potential target for the treatment of preeclampsia.