Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene
Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene
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DOI：
10.1210/jc.2007-1736
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发表时间：
2008-03-01
影响因子：
5.8
通讯作者：
Myers, Evan R.
中科院分区：
文献类型：
--
作者：
Legro, Richard S.;Barnhart, Huiman X.;Myers, Evan R.
内容：克罗米芬和胰岛素增敏剂如二甲双胍用于多囊卵巢综合征（PCOS）的促排卵，但排卵反应是可变的，这种变化的原因知之甚少。目的：我们的目的是确定预测性遗传多态性和排卵反应的其他决定因素。设计：这是一项多中心随机临床试验的子研究。本研究在学术医学中心及其附属机构进行。参与者：共312名PCOS妇女被纳入研究。主要结果测量：进行历史，生物统计学，生化和遗传参数。结果：我们发现，STK 11基因（在肝脏中表达;也称为LKB 1）中单核苷酸多态性的C等位基因与二甲双胍治疗的PCOS女性的排卵机会显著降低相关。在每个周期排卵分析中，比较C/C基因型与G/G基因型的校正比值比（OR）为0.30[95%置信区间（CI）0.14，0.66]，C/C基因型与G/G基因型的OR也为0.30（95% CI 0.14，0.66）。在对二甲双胍治疗受试者的分析中，我们发现排卵的女性百分比随着G等位基因的数量而增加：48%（21例中的10例）的C/C女性，67%（48例中的32例）的C/G女性和79%（19例中的15例）的G/G女性排卵。我们还发现，排卵频率增加与较低的体重指数（BMI）相关[校正OR为2.36（95% CI 1.65，3.36）和2.05（95% CI 1.46，2.88），分别用于比较BMI小于30与BMI等于或大于35，BMI 30-34与BMI等于或大于35，在每个周期的排卵分析中]，较低的游离雄激素指数（FAI）[FAI = 10的调整OR为1.59（95%CI 1.17，2.18）< 10 vs. FAI >]，以及较短的尝试受孕时间[= 1.5年的调整OR为1.63（95%CI 1.20，2.21< 1.5 vs. >）]。我们已经证明了STK 11（一种在肝脏中表达并与二甲双胍作用有关的激酶基因）的多态性，在一项前瞻性随机试验中，与单用甲孕酮治疗的排卵反应有关。与可变因素变化的影响的相互作用（e。G. BMI或FAI）需要进一步研究。
Context: Clomiphene and insulin sensitizers such as metformin are used to induce ovulation in polycystic ovary syndrome ( PCOS), but the ovulatory response is variable, and the causes of this variation are poorly understood.Objective: Our objective was to identify predictive genetic polymorphisms and other determinants of ovulatory response.Design: This was a substudy of a multicenter randomized clinical trial.Setting: This study was performed at academic medical centers and their affiliates.Participants: A total of 312 women with PCOS were included in the study.Main Outcome Measures: Historical, biometric, biochemical, and genetic parameters were performed.Results: We found that the C allele of a single nucleotide polymorphism in the STK11 gene ( expressed in liver; also known as LKB1) was associated with a significantly decreased chance of ovulation in PCOS women treated with metformin. In an analysis of ovulation per cycle, the adjusted odds ratio ( OR) comparing the C/C genotype to the G/G genotype was 0.30[95% confidence interval (CI) 0.14, 0.66], and the OR for the C/C genotype vs. the G/G genotype was also 0.30 ( 95% CI 0.14, 0.66). In an analysis of metformin-treated subjects, we found that the percentage of women who ovulated increased with the number of G alleles present: 48% ( 10 of 21) of C/C women, 67% ( 32 of 48) of C/G women, and 79% ( 15 of 19) of G/G women ovulated. We also found that increased frequency of ovulation was associated with lower body mass index (BMI) [adjusted OR of 2.36(95% CI 1.65, 3.36) and 2.05 ( 95% CI 1.46, 2.88), respectively, for comparisons of BMI less than 30 vs. BMI equal to or more than 35, BMI 30-34 vs. BMI equal to or more than 35, in the analysis of ovulation per cycle], a lower free androgen index (FAI) [adjusted OR of 1.59 ( 95% CI 1.17, 2.18) for FAI < 10 vs. FAI >= 10], and a shorter duration of attempting conception [adjusted OR of 1.63 ( 95% CI 1.20, 2.21) for < 1.5 vs. >= 1.5 yr].Conclusions: We have demonstrated that a polymorphism in STK11, a kinase gene expressed in liver and implicated in metformin action, is associated with ovulatory response to treatment with met formin alone in a prospective randomized trial. The interaction with the effects of changes in modifiable factors (e. g. BMI or FAI) requires further study.