Carroll Christopher L, Sala Kathleen A, Zucker Aaron R, Schramm Craig M
Department of Pediatrics, Connecticut Children's Medical Center, 282 Washington Street, Hartford, CT 06106, USA.
J Asthma. 2012 Aug;49(6):563-8. doi: 10.3109/02770903.2012.701362.
Children with asthma and respiratory failure comprise a small but significant subset of children with acute asthma. In addition to clinical and historical factors that have been associated with respiratory failure, there may also be genetic factors that predispose some asthmatic children to intubation and mechanical ventilation. However, this has not previously been assessed in this population. We hypothesized that genetic polymorphisms of the β(2)-adrenergic receptor (ADRβ(2)) are associated with intubation and mechanical ventilation in children with asthma.
We performed genotyping of the ADRβ(2) in a pooled cohort of 104 children admitted to the intensive care unit (ICU) with a severe asthma exacerbation between 2002 and 2008. Genotype of the ADRβ(2) was compared with intubation for respiratory failure.
At amino acid position 16, 33% (n = 34) of children were homozygous for the glycine allele (Gly16Gly), 15% (n = 16) were homozygous for the arginine allele (Arg16Arg), and 52% (n = 54) were heterozygous (Arg16Gly). At amino acid position 27, 54% (n = 56) of children were homozygous for the glutamine allele (Gln27Gln), 8% (n = 8) were homozygous for the glutamic acid allele (Glu27Glu), and 38% (n = 40) were heterozygous (Gln27Glu). The haplotypes at these positions were Arg16Gly-Gln27Gln (29%, n = 30), Arg16Gly-Gln27Glu (22%, n = 23), Gly16Gly-Gln27Glu (16%, n = 17), Arg16Arg-Gln27Gln (16%, n = 17), Gly16Gly-Gln27Gln (9%, n = 9), and Gly16Gly-Glu27Glu (8%, n = 8). Twelve children in this cohort were intubated for respiratory failure. Intubation was not associated with age, obesity, race/ethnicity, or NHBLI asthma classification. However, children with the Arg16Gly-Gln27Gln haplotype were significantly more likely to be intubated and mechanical ventilated (OR = 4.2; 95% CI = 1.2-14.5; p = .036) than children with other haplotypes of the ADRβ(2). When examining the subset of intubated children, those with the Arg16Gly-Gln27Gln haplotype trended towards longer ICU length of stay (329 ± 270 vs. 124 ± 57 hours; p = .09), but this was not statistically significant.
Children with the Arg16Gly-Gln27Gln haplotype of the ADRβ(2) were four times more likely to be intubated and mechanically ventilated during severe asthma exacerbations. Genetic factors may influence the development of a more severe asthma phenotype during acute exacerbations.
患有哮喘和呼吸衰竭的儿童是急性哮喘儿童中的一个小但重要的亚组。除了与呼吸衰竭相关的临床和病史因素外，可能还存在一些遗传因素，使某些哮喘儿童易发生插管和机械通气。然而，此前尚未在该人群中对此进行评估。我们假设β₂肾上腺素能受体（ADRβ₂）的基因多态性与哮喘儿童的插管和机械通气有关。
我们对2002年至2008年间因严重哮喘加重入住重症监护病房（ICU）的104名儿童的合并队列进行了ADRβ₂基因分型。将ADRβ₂的基因型与因呼吸衰竭进行的插管情况进行比较。
在第16位氨基酸处，33%（n = 34）的儿童为甘氨酸等位基因纯合子（Gly16Gly），15%（n = 16）为精氨酸等位基因纯合子（Arg16Arg），52%（n = 54）为杂合子（Arg16Gly）。在第27位氨基酸处，54%（n = 56）的儿童为谷氨酰胺等位基因纯合子（Gln27Gln），8%（n = 8）为谷氨酸等位基因纯合子（Glu27Glu），38%（n = 40）为杂合子（Gln27Glu）。这些位置的单倍型为Arg16Gly - Gln27Gln（29%，n = 30）、Arg16Gly - Gln27Glu（22%，n = 23）、Gly16Gly - Gln27Glu（16%，n = 17）、Arg16Arg - Gln27Gln（16%，n = 17）、Gly16Gly - Gln27Gln（9%，n = 9）和Gly16Gly - Glu27Glu（8%，n = 8）。该队列中有12名儿童因呼吸衰竭进行了插管。插管与年龄、肥胖、种族/民族或美国国立卫生研究院心肺血液研究所（NHBLI）哮喘分类无关。然而，与ADRβ₂其他单倍型的儿童相比，具有Arg16Gly - Gln27Gln单倍型的儿童进行插管和机械通气的可能性显著更高（比值比[OR] = 4.2；95%置信区间[CI] = 1.2 - 14.5；p = 0.036）。在检查插管儿童亚组时，具有Arg16Gly - Gln27Gln单倍型的儿童在ICU的住院时间有延长趋势（329 ± 270小时对124 ± 57小时；p = 0.0９），但这无统计学意义。
具有ADRβ₂的Arg16Gly - Gln27Gln单倍型的儿童在严重哮喘加重期间进行插管和机械通气的可能性高四倍。遗传因素可能影响急性加重期间更严重哮喘表型的发展。
