The association among cytochrome P450 3A, progesterone receptor polymorphisms, plasma 17-alpha hydroxyprogesterone caproate concentrations, and spontaneous preterm birth
The association among cytochrome P450 3A, progesterone receptor polymorphisms, plasma 17-alpha hydroxyprogesterone caproate concentrations, and spontaneous preterm birth
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DOI：
10.1016/j.ajog.2017.05.019
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发表时间：
2017-09-01
影响因子：
9.8
通讯作者：
Ramin, Susan M.
中科院分区：
文献类型：
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作者：
Bustos, Martha L.;Caritis, Steve N.;Ramin, Susan M.
背景技术：妊娠< 37周出生的婴儿受到公共卫生关注，因为与早产相关的并发症是< 5岁儿童死亡的主要原因，也是发病和终身残疾的主要原因。在有自发性早产史的妇女中，给予17-α-羟基孕酮己酸酯可使早产率降低33%。我们以前证明，17-α-羟孕酮己酸酯的血浆浓度在孕妇中变化很大，17-α-羟孕酮己酸酯血浆浓度在最低四分位数的妇女的自发性早产率为40%，而浓度较高的妇女的自发性早产率为25%。因此，血浆浓度是决定药物疗效的重要因素，但17-α-己酸羟孕酮血浆浓度变化如此之大的原因尚不清楚。目的：（1）确定17 α-羟基孕酮己酸酯血浆浓度与CYP 3A 4和CYP 3A 5单核苷酸多态性之间的关系，（2）检测孕酮受体单核苷酸多态性与自发性早产之间的关系，（3）研究孕酮受体单核苷酸多态性与自发性早产之间的关系。和（3）检验血浆17-α-羟孕酮己酸酯浓度与自发性早产之间的关联是否因孕酮受体单核苷酸多态性而异。在这项二次分析中，我们评估了268名接受17-α-羟基孕酮己酸酯治疗的孕妇的遗传多态性，她参加了一项安慰剂对照试验，以评估补充omega-3对有自发性早产史的妇女的益处。在妊娠25-28周之间，在至少5次注射17-α-羟孕酮己酸酯后，测量17-α-羟孕酮己酸酯的血浆谷浓度。我们从母亲的血液样本中提取DNA，并使用TaqMan对样本进行基因分型（Applied Biosystems，Foster City，CA）单核苷酸多态性基因分型试验，用于以下单核苷酸多态性：CYP 3A 4 *1B、CYP 3A 4 *1G、CYP 3A 4 *22和CYP 3A 5 *3;以及用于孕酮受体的rs 578029、rs 471767、rs666553、rs 503362和rs 500760。我们在多变量分析中调整了孕前体重指数、种族和治疗组。使用一般线性模型，对每个SNP的基因型的17-α-羟孕酮己酸酯血浆浓度的差异进行了评估。孕激素受体单核苷酸多态性和自发性早产的频率之间的关联进行了Logistic回归分析。一个逻辑模型也测试了17-α-羟基孕酮己酸浓度与每个孕激素受体单核苷酸多态性之间的相互作用对自发性早产结局的影响。α单核苷酸多态性 * 22、* 1G、* 1B和 * 3与17-α-己酸羟孕酮血浆谷浓度之间的关联没有统计学意义（P值分别为0.68、0.44、0.08和0.44）。在校正的logistic回归模型中，孕激素受体单核苷酸多态性rs 578029、rs 471767、rs666553、rs 503362和rs 500760与自发性早产的频率无关（P分别为0.29、0.10、0.76、0.09和0.43）。低血浆17-α-羟孕酮己酸酯谷浓度与自发性早产发生率较高相关（比值比，0.78; 95%可信比，0.61-0.99;四分位数趋势P = 0.04），但是与孕酮受体单核苷酸多态性rs 578029、rs 471767、rs666553、rs 503362和rs 500760（P分别为0.13，0.08，0.10，0.08和0.13）.结论：反复自发性早产的频率似乎与17-α-己酸羟孕酮血浆谷浓度有关。然而，谷17 α己酸羟孕酮血浆浓度的广泛变化并不归因于CYP 3A 4和CYP 3A 5基因的多态性。孕激素受体多态性不能预测17-α-羟孕酮己酸酯的疗效。该二次分析的局限性包括我们的样本量相对较小（n = 268），并且种族由患者自我报告。
BACKGROUND: Infants born < 37 weeks' gestation are of public health concern since complications associated with preterm birth are the leading cause of mortality in children< 5 years of age and a major cause of morbidity and lifelong disability. The administration of 17-alpha hydroxyprogesterone caproate reduces preterm birth by 33% in women with history of spontaneous preterm birth. We demonstrated previously that plasma concentrations of 17-alpha hydroxyprogesterone caproate vary widely among pregnant women and that women with 17-alpha hydroxyprogesterone caproate plasma concentrations in the lowest quartile had spontaneous preterm birth rates of 40% vs rates of 25% in those women with higher concentrations. Thus, plasma concentrations are an important factor in determining drug efficacy but the reason 17-alpha hydroxyprogesterone caproate plasma concentrations vary so much is unclear. Predominantly, 17-alpha hydroxyprogesterone caproate is metabolized by CYP3A4 and CYP3A5 enzymes.OBJECTIVE: We sought to: (1) determine the relation between 17alpha hydroxyprogesterone caproate plasma concentrations and single nucleotide polymorphisms in CYP3A4 and CYP3A5; (2) test the association between progesterone receptor single nucleotide polymorphisms and spontaneous preterm birth; and (3) test whether the association between plasma concentrations of 17-alpha hydroxyprogesterone caproate and spontaneous preterm birth varied by progesterone receptor single nucleotide polymorphisms.STUDY DESIGN: In this secondary analysis, we evaluated genetic polymorphism in 268 pregnant women treated with 17-alpha hydroxyprogesterone caproate, who participated in a placebo-controlled trial to evaluate the benefit of omega-3 supplementation in women with history of spontaneous preterm birth. Trough plasma concentrations of 17-alpha hydroxyprogesterone caproate were measured between 25-28 weeks of gestation after a minimum of 5 injections of 17-alpha hydroxyprogesterone caproate. We extracted DNA from maternal blood samples and genotyped the samples using TaqMan (Applied Biosystems, Foster City, CA) single nucleotide polymorphism genotyping assays for the following single nucleotide polymorphisms: CYP3A4*1B, CYP3A4*1G, CYP3A4*22, and CYP3A5*3; and rs578029, rs471767, rs666553, rs503362, and rs500760 for progesterone receptor. We adjusted for prepregnancy body mass index, race, and treatment group in a multivariable analysis. Differences in the plasma concentrations of 17-alpha hydroxyprogesterone caproate by genotype were evaluated for each CYP single nucleotide polymorphism using general linear models. The association between progesterone receptor single nucleotide polymorphisms and frequency of spontaneous preterm birth was tested using logistic regression. A logistic model also tested interaction between 17-alpha hydroxyprogesterone caproate concentrations with each progesterone receptor single nucleotide polymorphism for the outcome of spontaneous preterm birth.RESULTS: The association between CYP single nucleotide polymorphisms * 22, * 1G, * 1B, and * 3 and trough plasma concentrations of 17-alpha hydroxyprogesterone caproate was not statistically significant (P =.68,.44,.08, and.44, respectively). In an adjusted logistic regression model, progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 were not associated with the frequency of spontaneous preterm birth (P =.29,.10,.76,.09, and.43, respectively). Low trough plasma concentrations of 17-alpha hydroxyprogesterone caproate were statistically associated with a higher frequency of spontaneous preterm birth (odds ratio, 0.78; 95% confidence ratio, 0.61-0.99; P =.04 for trend across quartiles), however no significant interaction with the progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 was observed (P =.13,.08,.10,.08, and.13, respectively).CONCLUSION: The frequency of recurrent spontaneous preterm birth appears to be associated with trough 17-alpha hydroxyprogesterone caproate plasma concentrations. However, the wide variation in trough 17alpha hydroxyprogesterone caproate plasma concentrations is not attributable to polymorphisms in CYP3A4 and CYP3A5 genes. Progesterone receptor polymorphisms do not predict efficacy of 17-alpha hydroxyprogesterone caproate. The limitations of this secondary analysis include that we had a relative small sample size (n = 268) and race was self-reported by the patients.