人类β防御素基因簇拷贝数的变异是否与早产有关？

Is variation in copy number of the human beta defensin gene cluster associated with preterm birth?

机构信息

Research Department of Maternal and Fetal Medicine, Institute for Women's Health, University College London, London, UK; Infection, Immunity, Inflammation and Physiological Medicine, Institute of Child Health, University College London, London, UK.

Department of Genetics, University of Leicester, Leicester, UK.

出版信息

Lancet. 2015 Feb 26;385 Suppl 1:S47. doi: 10.1016/S0140-6736(15)60362-2.

DOI:10.1016/S0140-6736(15)60362-2

PMID:26312869

Abstract

BACKGROUND

Increased expression of antimicrobial peptides including human beta defensins (HBD) has been reported in the amniotic fluid and vaginal secretions of women who deliver preterm. We have previously shown that these women have increased first trimester serum HBD2. The gene encoding HBD2, DEFB4A, is part of a defensin beta (DEFB) cluster on chromosome 8 that is variable in copy number. Increased serum HBD2 is associated with increased DEFB copy number. We aimed to test the hypothesis that variation in DEFB copy number is associated with preterm birth.

METHODS

In a retrospective, case-control study, genomic DNA and serum were extracted from blood collected from white European women at 11-13 weeks' gestation attending King's College Hospital between March 1, 2006, and Sept 30, 2010. DEFB copy number was determined by paralogue ratio test. Serum HBD2 concentration was measured by ELISA. Data were analysed with Pearson correlation (Excel, version 2010) and binary logistic regression (SPSS, version 20).

FINDINGS

Cases were 102 women who either delivered preterm in the index pregnancy or had a history of preterm delivery. Controls were 152 women who had had at least one previous term delivery and delivered at term in the index pregnancy; they had no history of preterm birth. Modal copy number was 4 (range 2-7). Serum was available from 140 women (30 cases, 54 controls, 56 not included in the genetic association study). Median HBD2 concentration was 761·5 pg/mL (IQR 449·6-1232·0). There was no association between DEFB copy number and preterm birth, nor was there a correlation between copy number and serum HBD2 concentration.

INTERPRETATION

Although variation in HBD2 protein expression in the first trimester might be useful to predict risk of preterm birth, we found no association between DEFB copy number and preterm birth. Nor did we find a correlation between DEFB copy number and serum HBD2 expression in the first trimester of pregnancy; this might be due to variation in regulatory sequences-some of which are progesterone and oestrogen sensitive-between individual copies.

FUNDING

Wellcome Trust, Wellbeing of Women.

摘要

背景

有研究报道，在早产孕妇的羊水和阴道分泌物中，抗菌肽（包括人β防御素（HBD）在内）的表达增加。我们之前已经表明，这些女性在孕早期血清 HBD2 水平升高。编码 HBD2 的基因 DEFB4A 是染色体 8 上防御素β（DEFB）簇的一部分，其拷贝数存在变异性。血清 HBD2 水平升高与 DEFB 拷贝数增加相关。我们旨在检验假设，即 DEFB 拷贝数的变化与早产有关。

方法

在一项回顾性病例对照研究中，从 2006 年 3 月 1 日至 2010 年 9 月 30 日在国王学院医院就诊的白种欧洲孕妇 11-13 周妊娠时采集的血液中提取基因组 DNA 和血清。通过等位基因比例测试确定 DEFB 拷贝数。通过 ELISA 测量血清 HBD2 浓度。使用 Pearson 相关分析（Excel，版本 2010）和二项逻辑回归（SPSS，版本 20）进行数据分析。

结果

病例组为 102 名孕妇，其中 52 名孕妇在本次妊娠中早产，50 名孕妇在本次妊娠中有早产史。对照组为 152 名孕妇，在本次妊娠中有至少一次足月分娩史，且本次妊娠足月分娩，且无早产史。中位数拷贝数为 4（范围 2-7）。有 140 名妇女的血清可用（30 例，54 例对照，56 例未纳入遗传关联研究）。HBD2 浓度中位数为 761.5pg/ml（四分位距 449.6-1232.0）。DEFB 拷贝数与早产之间无关联，拷贝数与孕早期血清 HBD2 浓度之间也无相关性。这可能是由于个体拷贝之间的调节序列（其中一些对孕激素和雌激素敏感）存在变异性所致。