The Early Development of Wheeze Environmental Determinants and Genetic Susceptibility at 17q21
The Early Development of Wheeze Environmental Determinants and Genetic Susceptibility at 17q21
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DOI：
10.1164/rccm.201507-1493oc
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发表时间：
2016-04-15
影响因子：
24.7
通讯作者：
Ege, Markus J.
中科院分区：
文献类型：
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作者：
Loss, Georg J.;Depner, Martin;Ege, Markus J.
理由：在农场长大可以预防儿童哮喘和早期喘息。病毒触发的婴儿期喘息可预测与染色体17q21相关的遗传性哮喘风险个体的哮喘。目的：测试出生第一年感染和喘息的环境决定因素，17q21之前这些关联的潜在改变，以及这些因素对不同喘息轨迹的影响。方法：我们跟踪了欧洲农村地区983名儿童从出生到6岁。在第一年的每周日记中记录了喘息、鼻炎、发烧和环境暴露的症状。6岁时的哮喘被定义为曾经报告过医生的诊断。在17q21与ORMDL3(Rs8076131)和GSDMB(rs7216389，rs2290400)相关的单核苷酸多态性被分型。测量和主要结果：在已知哮喘危险等位基因携带者(例如，rs8076131)的携带者中，早期喘息与兄妹的存在正相关(调整后的优势比[AOR]，1.53；95%可信区间[CI]，1.16-2.01)。暴露在农场动物棚中与喘息呈负相关(AOR，0.44；95%CI，0.33-0.60)。这两种效应在3岁以下无哮喘发作的儿童中也有相似的观察结果(AOR，1.71[95%CI，1.09-2.67]；AOR，0.48[95%CI，0.30-0.76]。结论：这些发现提示染色体17q21基因座与喘息和哮喘常见的急性呼吸道阻塞有关。以前发现的哮喘风险等位基因是那些易受环境影响的等位基因。因此，这种基因-环境相互作用揭示了17q21的两个方面：相同的基因构成遗传风险并允许环境保护，从而为未来的预防策略提供了选择。
Rationale: Growing up on a farm protects from childhood asthma and early wheeze. Virus-triggered wheeze in infancy predicts asthma in individuals with a genetic asthma risk associated with chromosome 17q21.Objectives: To test environmental determinants of infections and wheeze in the first year of life, potential modifications of these associations by 17q21, and the implications for different trajectories of wheeze.Methods: We followed 983 children in rural areas of Europe from birth until age 6 years. Symptoms of wheeze, rhinitis, fever, and environmental exposures were documented with weekly diaries during year 1. Asthma at age 6 was defined as ever having a reported doctor's diagnosis. Single-nucleotide polymorphisms related to ORMDL3 (rs8076131) and GSDMB (rs7216389, rs2290400) at 17q21 were genotyped.Measurements and Main Results: Early wheeze was positively associated with presence of older siblings among carriers of known asthma risk alleles at 17q21 (e.g., rs8076131) (adjusted odds ratio [aOR], 1.53; 95% confidence interval [CI], 1.16-2.01). Exposure to farm animal sheds was inversely related to wheeze (aOR, 0.44; 95% CI, 0.33-0.60). Both effects were similarly observed in children with transient wheeze up to age 3 years without subsequent development of asthma (aOR, 1.71 [95% CI, 1.09-2.67]; and aOR, 0.48 [95% CI, 0.30-0.76], respectively).Conclusions: These findings suggest that the chromosome 17q21 locus relates to episodes of acute airway obstruction common to both transient wheeze and asthma. The previously identified asthma risk alleles are the ones susceptible to environmental influences. Thus, this gene-environment interaction reveals two faces of 17q21: The same genotype constitutes genetic risk and allows for environmental protection, thereby providing options for prospective prevention strategies.