Fine mapping of chromosome 12Q genes for asthma in CAMP

(申请者？S摘要)哮喘是一个重大的公共卫生问题。累积 有证据表明，遗传因素是这两种疾病的基本决定因素 哮喘的发展和严重程度。以家庭为基础的关联研究， 利用诸如传输不平衡检验等统计方法， 提供确定位置关系的最佳机会 哮喘表型的候选基因。儿童哮喘管理计划 (CAMP)是一项对1041名哮喘儿童进行的大型且成功的临床试验 最初年龄在5岁到12岁之间。这一宝贵的数据集包括678个完整的 父/子三元组和246个父/子对，可用于 哮喘候选体位的家族关联性研究。我们有 哮喘和血清总免疫球蛋白E与染色体标志物的关联 12q13-24在难民营人口中。这一地区也被证明是 全基因组扫描中的哮喘表型与更有限的关联 在其他人群中的研究。这一地区有许多有趣的地方 哮喘的位置候选基因包括：神经型一氧化氮合酶(NOS1)， 干扰素-γ、白三烯a-4水解酶、STAT6、β 核因子-Y亚单位(NFYB)、肥大细胞生长因子(MGF)和 胰岛素样生长因子1(IGF-1)。一种可变的链接模式 邻近基因座之间的不平衡需要识别 位置候选基因内的多个SNPs，以避免错误 排除候选基因。将使用以家庭为基础的关联方法 单个SNPs和相邻SNPs的单倍型，以缩小区域 可能包含易感基因，并在 定位候选基因，以确定哮喘、特应性、 以及哮喘的严重程度。将执行基于家庭的关联分析 哮喘和特应性相关表型包括：内科医生诊断的哮喘， 过敏性鼻炎，呼吸道反应性，支气管扩张剂反应，皮肤试验 反应性，外周血嗜酸细胞计数，总IgE和特异性IgE水平， 利用定位候选基因中识别的SNPs缩小 染色体L2q13-24，可能包含遗传影响的区域 哮喘和过敏症的发展。类似的分析将用于 哮喘严重程度表型包括哮喘起病年龄、肺活量、峰值 流量变异性、哮喘加重频率、住院和 急诊室就诊和全身皮质类固醇治疗要求 为了确定染色体L2q13-24位置候选基因SNPs是否包括 基因对哮喘严重程度的影响。最后，不同环境下的基因 将评估环境暴露之间的相互作用(由 调查问卷)、被动吸烟、毛茸茸的宠物和屋尘抗原 候选染色体L2q13-24上的SNP标记和测量 与哮喘严重程度相关的表型基因。

(Applicant?s Abstract) Asthma is a major public health problem. Cumulating evidence suggests that genetic factors are essential determinants of both the development and severity of asthma. Family-based association studies, utilizing statistical methods such as the transmission disequilibrium test, provide the best opportunity of identifying the relationship of positional candidate genes to asthma phenotypes. The Childhood Asthma Management Program (CAMP) is a large and successful clinical trial of 1041 asthmatic children initially aged five to twelve. This valuable data set includes 678 complete parent/child trios and 246 parent/child pairs which can be utilized for family-based association studies on asthma positional candidates. We have demonstrated linkage to asthma and total serum IgE to markers on chromosome l2q13-24 in the CAMP population. This region has also been demonstrated to be linked to asthma phenotypes in whole genome scans and more limited linkage studies in other populations. The region contains numerous interesting positional candidate genes for asthma including: neural NO synthase (NOS 1), interferon-gamma (IFN-gamma), leukotriene a-4 hydrolase (LTA4H), STAT6, beta subunit of nuclear factor-Y (NFYB), mast cell growth factor (MGF), and insulin-like growth factor 1 (IGF-1). A variable pattern of linkage disequilibriurn between nearby genetic loci necessitates the identification of multiple SNPs within a positional candidate gene, in order to avoid falsely excluding the candidate gene. Family-based association methods will be used with individual SNPs, and with haplotypes of adjacent SNPs, to narrow regions likely to contain susceptibility genes and to test variants within the positional candidate genes to identify genetic determinants of asthma, atopy, and asthma severity. Family-based association analyses will be performed with asthma and atopy related phenotypes including: physician diagnosed asthma, allergic rhinitis, airway responsiveness, bronchodilator response, skin test reactivity, peripheral blood eosinophil count, total and specific IgE levels, using SNPs identified within positional candidate genes to narrow the chromosome l2q13-24, region likely to contain genetic influences on the development of asthma and atopy. Similar analyses will be performed with asthma severity phenotypes including age of onset of asthma, spirometry, peak flow variability, frequency of asthma exacerbations, hospitalizations and emergency room visits, and requirement for systemic corticosteroid treatment to determine if the chromosome l2q13-24 positional candidate gene SNPs include genetic influences on the severity of asthma. Finally, genotype by environment interactions will be assessed between environmental exposures (determined by questionnaire), passive smoking, furry pets, and house dust antigen measurements and SNP markers within chromosome l2q13-24 positional candidate genes on phenotypes related to asthma severity.