Alterations in oestrogen metabolism: implications for higher penetrance of familial pulmonary arterial hypertension in females

Abstract

Mutations in bone morphogenetic protein receptor type 2 (BMPR2) cause familial pulmonary arterial hypertension (FPAH), but the penetrance is reduced and females are significantly overrepresented. In addition, gene expression data implicating the oestrogen-metabolising enzyme CYP1B1 suggests a detrimental role of oestrogens or oestrogen metabolites. We examined genetic and metabolic markers of altered oestrogen metabolism in subjects with a BMPR2 mutation. Genotypes for CYP1B1 Asn453Ser (N453S) were determined for 140 BMPR2 mutation carriers (86 females and 54 males). Nested from those subjects, a case-control study of urinary oestrogen metabolite levels (2-hydroxyoestrogen (2-OHE) and 16alpha-hydroxyoestrone (16alpha-OHE(1))) was conducted in females (five affected mutation carriers versus six unaffected mutation carriers). Among females, there was four-fold higher penetrance among subjects homozygous for the wild-type genotype (N/N) than those with N/S or S/S genotypes (p = 0.005). Consistent with this finding, the 2-OHE/16alpha-OHE(1) ratio was 2.3-fold lower in affected mutation carriers compared to unaffected mutation carriers (p = 0.006). Our findings suggest that variations in oestrogens and oestrogen metabolism modify FPAH risk. Further investigation of the role of oestrogens in this disease with profound sex bias may yield new insights and, perhaps, therapeutic interventions.

FIGURE 1

Ratio of urinary 2-hydroxyoestrogen (2-OHE) to 16α-hydroxyoestrone (16α-OHE₁) in affected BMPR2 mutation carriers (AMCs) versus unaffected BMPR2 mutation carriers (UMCs) (ng per mg creatinine per mL). AMCs have a significantly reduced ratio compared to UMCs (p=0.006). Data points and box plots are shown for each group. Box and whisker plots represent the median value, interquartile range and highest and lowest values.

FIGURE 2

Cumulative mortality curve for all affected BMPR2 mutation carriers in the Vanderbilt familial pulmonary arterial hypertension research registry, represented as the percentage of all subjects by sex (▲: females; □: males) deceased at a given age. There is a statistically significant difference in the per cent mortality by age between the two groups prior to age 18 yrs (shaded; p=0.031). The difference in per cent mortality between males and females prior to age 18 yrs reflects a lower prevalence among females in childhood compared with males.