Fine mapping of genes underlying asthma and eosinophilia

哮喘是澳大利亚第四大最常见的慢性疾病，发病率正在上升。众所周知，遗传因素是疾病风险的重要修饰因素，文献中报道了几种基因参与引起哮喘或改变对治疗的反应。免疫球蛋白E （IgE）水平和嗜酸性粒细胞计数是已知哮喘患者血液中升高的两个因素。在我们小组的两项研究中，一项是家庭哮喘，另一项是健康的青春期双胞胎，我们发现这些指标与基因组中的两个不同区域有基因联系。对这些区域的进一步研究发现了几个可能与这种联系有关的基因。在目前的研究中，我们计划测试哪些候选基因实际上导致了IgE水平或嗜酸性粒细胞计数的升高。该方法是比较儿童中表达该表型的假定基因与其父母中的基因的频率。每个孩子从父亲那里得到一个基因的副本，从母亲那里得到一个基因的副本，构成了一个完整的基因型（两个可能不同的基因版本或等位基因）。由于父母双方只遗传了一个等位基因给孩子，所以父母双方剩下的等位基因可以用来创造一个正常的对照基因型，保证来自与哮喘孩子相同的种族背景。因此，我们将在那些先前的DNA在我们早期的研究中已经用尽的家庭中收集替代血液样本。我们将提取DNA，并在我们认为最有可能参与嗜酸性粒细胞计数或IgE水平的两个区域的6个基因上测量父母和孩子的基因型。这种基于家庭的测试将使我们能够确定哪些基因与我们的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。鉴定与哮喘有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.