Fine mapping of genes underlying asthma and eosinophilia

哮喘是澳大利亚第四种最常见的慢性病，而且发病率正在上升。众所周知，遗传因素是疾病风险的重要调节因素，文献中已有几个基因被报道与引起哮喘或改变对治疗的反应有关。免疫球蛋白E(IgE)水平和嗜酸性粒细胞计数是已知的哮喘患者血液中升高的两个因素。在我们团队的两项研究中，一项是关于家族中的哮喘，另一项是健康的青少年双胞胎，我们表明这些指标与基因组中的两个不同区域有遗传联系。对这些区域的仔细检查发现了几个可能导致这种联系的基因。在目前的研究中，我们计划测试这些候选基因中的哪些实际上会导致IgE水平或嗜酸性粒细胞计数升高。方法是比较表达该表型的儿童与其父母的假定基因的频率。每个孩子从父亲那里得到一个基因拷贝，从母亲那里得到一个拷贝，组成一个完整的基因(两个可能不同的基因版本或等位基因)。由于每个父母只把一个等位基因传递给孩子，所以每个父母剩下的等位基因可以用来创造一个正常的对照基因，保证来自与哮喘儿童相同的种族背景。因此，我们将收集那些先前DNA在我们早期研究中已经用完的家庭的替换血液样本。我们将提取DNA，并在我们认为最可能与嗜酸性粒细胞计数或IgE水平有关的两个区域的6个基因上测量父母和孩子的基因类型。这项以家庭为基础的测试将使我们能够确定哪些基因与我们人群中的哮喘真正相关。我们还将测试这些基因是否与其他被认为是哮喘风险因素的基因相互作用。识别与哮喘相关的新基因将有助于理解并最终治疗这种疾病。

Asthma is the fourth most common chronic disease in Australia, and is increasing in incidence. Genetic factors are known to be important modifiers of disease risk, and several genes have been reported in the literature as being involved in either causing asthma or altering response to therapy. Immunoglobulin E (IgE) level and eosinophil count are two factors known to be increased in the blood of asthmatics. In two studies by our group, one of asthma in families, the other of healthy adolescent twins, we showed these measures to be genetically linked to two different regions in the genome. Closer examination of these regions found several genes that might be responsible for the linkage. In the present study, we plan to test which of these candidate genes actually causes elevated IgE level or eosinophil count. The approach is to compare the frequency of a putative gene in a child expressing that phenotype to that in their parents. Each child receives one copy of a gene from the father, and one from the mother, making up a complete genotype (two possibly different versions or alleles of the gene). Since each parent transmitted only one allele to the child, the remaining allele from each parent can be used to create a normal control genotype, that is guaranteed to come from the same ethnic background as the asthmatic child. Therefore, we will collect replacement blood samples in those familes where all the previously DNA has been used up in our earlier study. We will extract DNA, and measure the genotypes of parents and children at the 6 genes in our two regions that we think most likely to be involved in eosinophil count or IgE level. This family based test will allow us to decide which genes are genuinely associated with asthma in our population. We will also test if these genes interact with other genes thought to be asthma risk factors. Identification of novel genes involved in asthma will help understand and ultimately treat this condition.