Alterations in oestrogen metabolism: implications for higher penetrance of familial pulmonary arterial hypertension in females.
Alterations in oestrogen metabolism: implications for higher penetrance of familial pulmonary arterial hypertension in females.
复制标题
DOI：
10.1183/09031936.00010409
复制
发表时间：
2009-11
期刊：
影响因子：
--
通讯作者：
Phillips JA 3rd
中科院分区：
文献类型：
--
作者：
Austin ED;Cogan JD;West JD;Hedges LK;Hamid R;Dawson EP;Wheeler LA;Parl FF;Loyd JE;Phillips JA 3rd
骨形态发生蛋白2型受体（BMPR2）的突变可引起家族性肺动脉高压（FPAH），但发病率降低，且女性明显多于男性。此外，涉及雌激素代谢酶CYP1B1的基因表达数据表明雌激素或雌激素代谢物的有害作用。我们研究了BMPR2突变受试者雌激素代谢改变的遗传和代谢标志物。对140例BMPR2突变携带者（86例女性和54例男性）进行了CYP1B1 Asn453Ser（N453S）基因型测定。从这些受试者中嵌套，在女性（5名受影响突变携带者与6名未受影响突变携带者）中进行了一项尿雌激素代谢产物水平（2-羟基雌激素（2-OHE）和16 α-羟基雌酮（16 α-OHE 1））的病例对照研究。在女性中，野生型基因型（N/N）纯合子的受试者中的突变率比N/S或S/S基因型高4倍（p = 0.005）。与这一发现一致，与未受影响的突变携带者相比，受影响的突变携带者的2-OHE/16 α-OHE 1比值低2.3倍（p = 0.006）。我们的研究结果表明，雌激素和雌激素代谢的变化改变FPAH的风险。进一步研究雌激素在这种具有深刻性别偏见的疾病中的作用可能会产生新的见解，也许，治疗干预。
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.
登录
查看更多内容
DOI：
10.1073/pnas.82.18.6295
发表时间：
1985-01-01
影响因子：
11.1
作者：
BRADLOW, HL;HERSHCOPF, RJ;FISHMAN, J
通讯作者：
FISHMAN, J
影响因子：
10.3
作者：
Missmer, SA;Eliassen, AH;Hankinson, SE
通讯作者：
Hankinson, SE
影响因子：
8.8
作者：
Cogan, JD;Vnencak-Jones, CL;Loyd, JE
通讯作者：
Loyd, JE
影响因子：
11.2
作者：
Belous, Alexandra R.;Hachey, David L.;Parl, Fritz F.
通讯作者：
Parl, Fritz F.
影响因子：
3.8
作者：
Greenlee, Heather;Chen, Yu;Ahsan, Habibul
通讯作者：
Ahsan, Habibul