Journal
EUROPEAN RESPIRATORY JOURNAL
Volume 34, Issue 5, Pages 1093-1099Publisher
EUROPEAN RESPIRATORY SOC JOURNALS LTD
DOI: 10.1183/09031936.00010409
Keywords
Bone morphogenetic protein receptor 2; CYP1B1; genetic polymorphism; oestrogen; pulmonary hypertension; sex
Categories
Funding
- National Institutes of Health
- National Heart, Lung, and Blood Institute [P01 HL72058, K12 RR.1 7697, P01 HL072058]
- Vanderbilt General Clinical Research Center [M01 RR 000095]
- NCRR/NIH (Nashville, TN, USA)
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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 16 alpha-hydroxyoestrone (16 alpha-OHE1)) 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/16 alpha-OHE1 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.
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