Key result
The CYP1B1 wild-type genotype (N/N) was associated with a four-fold higher penetrance of FPAH among female BMPR2 mutation carriers compared to N/S or S/S genotypes (p=0.005).
Why the study?
Do variations in the CYP1B1 genotype and estrogen metabolism modify the penetrance of familial pulmonary arterial hypertension in BMPR2 mutation carriers?
Case-Control (n=140)
Do variations in the CYP1B1 genotype and estrogen metabolism modify the penetrance of familial pulmonary arterial hypertension in BMPR2 mutation carriers?
Effect estimate: 4-fold higher penetrance
p-value: p=0.005
Variations in estrogen metabolism, specifically the CYP1B1 genotype and estrogen metabolite ratios, are associated with altered penetrance of familial pulmonary arterial hypertension in female BMPR2 mutation carriers.
May refine risk stratification in female BMPR2 carriers; hypothesis-generating and requires prospective validation before clinical adoption.
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.
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Austin et al. (2009) conducted a case-control in familial pulmonary arterial hypertension (n=140). CYP1B1 Asn453Ser (N453S) wild-type genotype (N/N) vs. N/S or S/S genotypes was evaluated on Penetrance of FPAH (4-fold higher penetrance, p=0.005). The CYP1B1 wild-type genotype (N/N) was associated with a four-fold higher penetrance of FPAH among female BMPR2 mutation carriers compared to N/S or S/S genotypes (p=0.005).
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