RT Journal Article
SR Electronic
T1 Alterations in oestrogen metabolism: implications for higher penetrance of familial pulmonary arterial hypertension in females
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1093
OP 1099
DO 10.1183/09031936.00010409
VO 34
IS 5
A1 E. D. Austin
A1 J. D. Cogan
A1 J. D. West
A1 L. K. Hedges
A1 R. Hamid
A1 E. P. Dawson
A1 L. A. Wheeler
A1 F. F. Parl
A1 J. E. Loyd
A1 J. A. Phillips III
YR 2009
UL http://erj.ersjournals.com/content/34/5/1093.abstract
AB 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 16α-hydroxyoestrone (16α-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/16α-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.