Palmer L J, Cookson W O, James A L, Musk A W, Burton P R
Genetic Epidemiology Unit, Division of Population Sciences, TVW Telethon Institute for Child Health Research, Perth, Western Australia.
Genet Epidemiol. 2001 Apr;20(3):356-72. doi: 10.1002/gepi.6.
Asthma is a common, complex human disease. Elevated serum immunoglobulin E (IgE) levels, elevated blood eosinophil counts, and increased airway responsiveness are physiological traits that are characteristic of asthma. Few studies have investigated major gene effects for these traits in a population-based sample. Further, it is not known if any putative major genes may be common to two or more of these traits. We investigated the existence and nature of major genes modulating asthma-associated quantitative traits in an Australian population-based sample of 210 Caucasian nuclear families. The sharing of these major genes was also investigated. Segregation analysis was based upon a Markov Chain Monte Carlo (Gibbs sampling) approach as implemented in the program BUGS v0.6. All models included adjustment for age, height, tobacco smoke exposure, and gender. The segregation of total IgE levels, blood eosinophil counts, and dose-response slope (DRS) of methacholine challenge were all consistent with major loci at which a recessive allele acted to increase or decrease the phenotype. The respective estimated frequencies of the recessive alleles were 68% (total IgE), 10% (blood eosinophil count), and 27% (DRS). Extensive modelling suggested that the major loci controlling total serum IgE levels, blood eosinophil counts, and airway responsiveness represent different genes. These data provide evidence, for the first time, of the existence of at least 3 distinct genetic pathways involving major gene effects on physiological traits closely associated with asthma. These results have implications for gene discovery programs.
哮喘是一种常见的复杂人类疾病。血清免疫球蛋白E（IgE）水平升高、血液嗜酸性粒细胞计数升高以及气道反应性增加是哮喘的生理特征。很少有研究在基于人群的样本中调查这些特征的主要基因效应。此外，尚不清楚是否有任何假定的主要基因可能是这些特征中的两个或更多个所共有的。我们在一个基于澳大利亚人群的210个白种人核心家庭样本中，研究了调节哮喘相关数量性状的主要基因的存在和性质。还研究了这些主要基因的共享情况。分离分析基于BUGS v0.6程序中实现的马尔可夫链蒙特卡罗（吉布斯抽样）方法。所有模型都对年龄、身高、烟草烟雾暴露和性别进行了调整。总IgE水平、血液嗜酸性粒细胞计数以及乙酰甲胆碱激发试验的剂量反应斜率（DRS）的分离均与隐性等位基因起作用以增加或减少表型的主要基因座一致。隐性等位基因的各自估计频率分别为68%（总IgE）、10%（血液嗜酸性粒细胞计数）和27%（DRS）。广泛的建模表明，控制总血清IgE水平、血液嗜酸性粒细胞计数和气道反应性的主要基因座代表不同的基因。这些数据首次提供了证据，证明至少存在3条不同的遗传途径，涉及对与哮喘密切相关的生理性状有主要基因效应。这些结果对基因发现计划具有启示意义。
