Supplementary Material for: Glucocorticoid Receptor Gene Variants and Neonatal Outcome in Very-Low-Birth-Weight Preterm Infants

<strong><em>Background:</em></strong> Induction of lung maturation by prenatal steroid treatment has become the standard of care for pregnant women at risk for preterm birth. In addition to the beneficial effects on lung maturation, prenatal steroids have been shown to reduce the incidence of neonatal death, necrotizing enterocolitis, sepsis, and intraventricular hemorrhage. However, little is known about the role of interindividual differences in corticoid sensitivity arising from polymorphisms in the glucocorticoid receptor <i>(GR)</i> gene. <b><i>Objectives:</i></b> To assess the impact of <i>GR</i> polymorphisms <i>N363S</i> (rs56149945), <i>R23K</i> (rs6190), and <i>BclI</i> (rs41423247) on neonatal outcome. <b><i>Methods:</i></b> The <i>GR</i> polymorphisms <i>N363S, R23K,</i> and <i>BclI</i> were examined in 10,490 very-low-birth-weight (VLBW) preterm infants from 49 German tertiary level neonatal units (German Neonatal Network, GNN) with respect to neonatal outcome. <b><i>Results:</i></b> Infants carrying the <i>BclI</i> genotype were at higher risk to develop bronchopulmonary dysplasia (BPD) (OR 1.12 per <i>BclI</i> allele, 95% CI: 1.02-1.23, p = 0.013) in a logistic regression model adjusted for gestational age, mechanical ventilation, and small for gestational age status. A similar relative risk was seen in the children (89.4%) who received antenatal betamethasone treatment (OR 1.16, 95% CI: 1.05-1.27, p = 0.003), whereas no such effect was detectable in infants without antenatal steroids. <i>N363S</i> and <i>R23K</i> did not show any stable association with neonatal outcome parameters. <b><i>Conclusion:</i></b> Except for a slightly higher risk of BPD in carriers of the <i>GR</i><i>BclI</i> variant, the <i>GR</i> gene polymorphisms <i>BclI, N363S,</i> and <i>R23K</i> did not affect neonatal outcome parameters in this large multicenter cohort of VLBW preterm infants.

**背景：** 产前类固醇治疗诱导肺成熟已成为存在早产风险孕妇的标准诊疗方案。除对肺成熟产生有益作用外，产前类固醇治疗还被证实可降低新生儿死亡、坏死性小肠结肠炎、败血症及脑室内出血的发生率。然而，由糖皮质激素受体（glucocorticoid receptor, GR）基因多态性所导致的个体间糖皮质激素敏感性差异，其相关作用机制目前仍鲜为人知。
**目的：** 评估GR基因多态性N363S（rs56149945）、R23K（rs6190）及BclI（rs41423247）对新生儿结局的影响。
**方法：** 纳入来自德国新生儿网络（German Neonatal Network, GNN）下属49家三级新生儿重症监护病房的10490名极低出生体重（very-low-birth-weight, VLBW）早产儿，检测其GR基因多态性N363S、R23K及BclI，并分析上述多态性与新生儿结局的关联。
**结果：** 在校正胎龄、机械通气及小于胎龄状态的logistic回归模型中，携带BclI基因型的婴儿发生支气管肺发育不良（bronchopulmonary dysplasia, BPD）的风险更高（每携带1个BclI等位基因的比值比OR=1.12，95%置信区间CI：1.02~1.23，P=0.013）。在接受产前倍他米松治疗的婴儿（占比89.4%）中观察到了相似的相对风险（OR=1.16，95%CI：1.05~1.27，P=0.003），而在未接受产前类固醇治疗的婴儿中未检测到此类效应。N363S与R23K均未显示出与新生儿结局指标存在稳定关联。
**结论：** 在本项大型多中心极低出生体重早产儿队列研究中，除GR基因BclI变异携带者发生BPD的风险轻度升高外，GR基因BclI、N363S及R23K多态性均未对新生儿结局指标产生影响。