CYP2D6 和 CYP2C9 基因多态性与早发型重度子痫前期及拉贝洛尔治疗反应的相关性。

Associations of polymorphisms of CYP2D6 and CYP2C9 with early onset severe pre-eclampsia and response to labetalol therapy.

机构信息

Department of Obstetrics, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, No. 251 Yaojiayuan Road, 100026, Beijing, People's Republic of China.

Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, No. 251 Yaojiayuan Road, 100026, Beijing, People's Republic of China.

出版信息

Arch Gynecol Obstet. 2018 Jul;298(1):125-132. doi: 10.1007/s00404-018-4791-8. Epub 2018 May 22.

DOI:10.1007/s00404-018-4791-8

PMID:29789925

Abstract

PURPOSE

Early onset preeclampsia (PPE) contributes to life-threatening maternal complications and fetal demise. Pharmacogenomics is a precision medicine, and metabolizing enzymes responsive to antihypertensive remains understudied. The aim of this study was to evaluate the associations of polymorphisms of cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) and cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) with PPE and the relationship among CYP2D6, CYP2C9 polymorphisms and response to labetalol therapy.

METHODS

Totally 105 gravidas diagnosed with PPE (case) and 103 healthy gravidas (control) were recruited between August 2013 and July 2016. Labetalol was given to control blood pressures (BP) with PPE. If labetalol administration alone did not exceed the mean dose and effectively controlled the BP, it would be considered to be valid (n = 75). Genotype and allele frequencies of CYP2C9 gene (rs1057910 and rs4918758) and CYP2D6 gene (rs1065852, rs28371725, rs35742686, and rs3892097) were analyzed by TaqMan PCR. Differences in the genotype and allele frequencies were compared between case-control groups, and the responsive and nonresponsive to labetalol in PPE.

RESULTS

Out of six variants, only CC and CT genotypes of the CYP2D6 variants (rs28371725) in PPE were significantly higher than those in the control group [18.1% (19/105) vs 14.6% (15/103); 56.2% (59/105) vs 42.7% (44/103); χ2 = 6.707]. However, there were no differences in maternal age, diastolic pressure, BMI, BW, serum triglyceride, and creatinine were observed among women with CC, CT, or TT genotype of CYP2D6 gene rs28371725 in the experimental group (all P > 0.05). Compared with the gravidas with CT or TT genotype of CYP2D6 gene rs28371725, those with CC genotype had longer gestational age [(32.5 ± 2.1) vs (29.5 ± 1.8) and (29.8 ± 2.2) weeks] and higher plasma albumin [(27.2 ± 9.3) vs (20.3 ± 10.4) and (22.5 ± 7.4) g/L], but lower systolic pressure and 24 h urine protein (LSD test, all P < 0.05). The G allele frequency in CYP2D6 gene rs1065852 nonresponsive to labetalol group was higher than that in responsive labetalol group [93.3% (56/60) vs 76.0% (114/150), χ2 = 8.351, P = 0.004].

CONCLUSIONS

The polymorphism of CYP2D6 gene rs28371725 may be associated with PPE, and the allele of G in CYP2D6 gene rs1065852 may be associated with the efficacy of labetalol in treatment of PPE.

摘要

目的

早发型先兆子痫（PE）可导致危及生命的母亲并发症和胎儿死亡。药物基因组学是一种精准医学，而对抗高血压的代谢酶仍研究不足。本研究旨在评估细胞色素 P450，家族 2，亚家族 D，多肽 6（CYP2D6）和细胞色素 P450，家族 2，亚家族 C，多肽 9（CYP2C9）的多态性与 PPE 的相关性，以及 CYP2D6、CYP2C9 多态性与拉贝洛尔治疗反应之间的关系。

方法

2013 年 8 月至 2016 年 7 月期间，共招募了 105 例诊断为 PPE（病例）和 103 例健康孕妇（对照组）。用拉贝洛尔控制 PPE 的血压。如果单独使用拉贝洛尔不超过平均剂量且有效控制血压，则认为有效（n=75）。通过 TaqMan PCR 分析 CYP2C9 基因（rs1057910 和 rs4918758）和 CYP2D6 基因（rs1065852、rs28371725、rs35742686 和 rs3892097）的基因型和等位基因频率。比较病例对照组、PPE 中拉贝洛尔反应性和非反应性之间的基因型和等位基因频率差异。

结果

在六个变体中，只有 CYP2D6 变体（rs28371725）的 CC 和 CT 基因型在 PPE 中显著高于对照组[18.1%（19/105）与 14.6%（15/103）；56.2%（59/105）与 42.7%（44/103）；χ2=6.707]。然而，在实验组中，CYP2D6 基因 rs28371725 的 CC、CT 或 TT 基因型的女性中，其母亲年龄、舒张压、BMI、BW、血清甘油三酯和肌酐均无差异（均 P>0.05）。与 CYP2D6 基因 rs28371725 的 CT 或 TT 基因型的孕妇相比，CC 基因型的孕妇有更长的胎龄[（32.5±2.1）比（29.5±1.8）和（29.8±2.2）周]和更高的血浆白蛋白[（27.2±9.3）比（20.3±10.4）和（22.5±7.4）g/L]，但收缩压和 24 小时尿蛋白较低（LSD 检验，均 P<0.05）。CYP2D6 基因 rs1065852 非反应性拉贝洛尔组的 G 等位基因频率高于反应性拉贝洛尔组[93.3%（56/60）与 76.0%（114/150），χ2=8.351，P=0.004]。