Association of a promoter variant of the haeme oxygenase-1 gene with hypertension in women.

OBJECTIVE

To examine the relationship between the gene for haeme oxygenase (HO)-1 (HMOX-1) and human essential hypertension, because both the acute and systemic induction of HMOX-1 have been suggested to attenuate vascular tone and blood pressure.

METHODS

We screened for sequence variations in HMOX-1 and conducted an association study, using these polymorphisms, in a large cohort (1998 individuals) representing the general Japanese population. RESULTS We sequenced HMOX-1 and found a T(-413)A polymorphism in the promoter region. The frequency of hypertensive individuals and the use of antihypertensive drugs were significantly greater in the AA genotype than in other genotypes among women: 45.5, 34.2, and 35.0% (P = 0.0099) and 23.4, 17.5, and 15.0% (P = 0.038), respectively, for the AA, AT, and TT genotypes, respectively. However, this association was not observed in men. Multiple logistic analyses indicated that the T(-413)A (AA/TA+TT) polymorphism, age, and body mass index affected the occurrence of hypertension in women. The odds ratio of the AA genotype for hypertension in women was 1.59 (P = 0.0058; 95% confidence interval 1.14 to 2.20). A luciferase reporter assay indicated that the A allele-promoter had eight-fold greater activity than the T allele promoter (P < 0.01).

CONCLUSIONS

The AA genotype of HMOX-1 is associated with an increased incidence of hypertension in women. Oestrogen attenuates vasoconstriction by increasing the expression of inducible nitric oxide synthase. As carbon monoxide, which is one of the products of HO-1, can attenuate nitric oxide-induced vasodilatation, a high expression of HO-1 may cause hypertension, especially in women.