Cord blood PRF1 methylation patterns and risk of lower respiratory tract infections in infants: findings from the Ulm Birth Cohort.
Cord blood PRF1 methylation patterns and risk of lower respiratory tract infections in infants: findings from the Ulm Birth Cohort.
复制标题
DOI：
10.1097/md.0000000000000332
复制
发表时间：
2015-01
期刊：
影响因子：
1.6
通讯作者：
Rothenbacher D
中科院分区：
文献类型：
--
作者：
Elgizouli M;Logan C;Nieters A;Brenner H;Rothenbacher D
补充数字内容可在文本中找到。 下呼吸道感染 (LRTI) 是儿童发病的主要原因。 DNA 甲基化提供了一种传递环境对基因组影响的机制，但其在 LRTI 中的潜在作用尚未得到充分研究。我们在德国出生队列中招募的第一年患有 LRTI 的儿童的脐带血 DNA 中，研究了免疫效应基因穿孔素-1 (PRF1) 增强子区域的甲基化模式，该基因编码细胞毒性 T 淋巴细胞 (CTL) 和自然杀伤细胞 (NK) 的细胞溶解分子。焦磷酸测序用于确定两阶段病例对照设计中目标胞嘧啶-磷酸-鸟嘌呤 (CpG) 的甲基化水平。病例被确定为在出生第一年发生≥2次医生记录的 LRTI 发作的儿童，对照组为没有发生过 2 次以上的儿童。发现组（n = 87）和复制组（n = 90）按性别和出生季节匹配的 1 个病例和 2 个对照组成三组。 Logistic 回归分析显示，在发现组（比值比 [OR] 每 1% 甲基化差异 1.24，95% 置信区间 [CI] 1.03–1.50）和复制组（OR 每 1% 甲基化差异 1.25，95% CI 1.04–1.50）中，对应于信号转导子和转录激活子 5 (STAT5) 响应增强子的 CpG 甲基化水平较高。对发现组和复制组中有小于 5 岁的兄弟姐妹进行调整后，OR 分别为 1.19 (95% CI 0.98–1.45) 和 1.25 (95% CI 1.04–1.50)。复制组中胎龄的调整对结果没有影响。相邻 CpG 的甲基化水平随母亲年龄、吸烟、教育程度和兄弟姐妹年龄 <5 岁的变化而变化。我们的数据支持脐带血 PRF1 增强子甲基化模式与婴儿随后发生 LRTI 风险之间的关联。 PRF1 增强子的特定 CpG 的甲基化水平根据母亲和家庭环境因素而变化，表明 DNA 甲基化在介导环境对基因功能的影响中发挥作用。
Supplemental Digital Content is available in the text Lower respiratory tract infections (LRTIs) are a major cause of morbidity in children. DNA methylation provides a mechanism for transmitting environmental effects on the genome, but its potential role in LRTIs is not well studied. We investigated the methylation pattern of an enhancer region of the immune effector gene perforin-1 (PRF1), which encodes a cytolytic molecule of cytotoxic T lymphocytes (CTLs) and natural killer cells (NK), in cord blood DNA of children recruited in a German birth cohort in association with LRTIs in the first year of life. Pyrosequencing was used to determine the methylation levels of target cytosine–phosphate–guanines (CpGs) in a 2-stage case–control design. Cases were identified as children who developed ≥2 episodes of physician-recorded LRTIs during the first year of life and controls as children who had none. Discovery (n = 87) and replication (n = 90) sets were arranged in trios of 1 case and 2 controls matched for sex and season of birth. Logistic regression analysis revealed higher levels of methylation at a CpG that corresponds to a signal transducer and activator of transcription 5 (STAT5) responsive enhancer in the discovery (odds ratio [OR] per 1% methylation difference 1.24, 95% confidence interval [CI] 1.03–1.50) and replication (OR per 1% methylation difference 1.25, 95% CI 1.04–1.50) sets. Adjustment for having siblings <5 years old in the discovery and replication sets produced ORs of 1.19 (95% CI 0.98–1.45) and 1.25 (95% CI 1.04–1.50), respectively. Adjustment for gestational age in the replication set had no influence on the results. Methylation levels at adjacent CpGs varied with maternal age, smoking, education, and having siblings <5 years old. Our data support an association between cord blood PRF1 enhancer methylation patterns and subsequent risk of LRTIs in infants. Methylation levels at specific CpGs of the PRF1 enhancer varied according to maternal and family environmental factors suggesting a role for DNA methylation in mediating environmental influences on gene function.