Investigation of the susceptibility gene for COPD by homozygosity fingerprinting method

阐明多基因疾病的致病基因是一个困难而又重要的课题。在这个领域中，全基因组关联的方法经常被使用。然而，该方法仅适用于频率较高的疾病，结果往往缺乏重复性。我们发明了针对多基因疾病的纯合子指纹方法。这是一种适用于隐性基因的非参数方法。我们用霍尔丹的泊松过程模型确定了染色体重组方法的几个参数，为鉴定来自少数祖先并现已传播到群体中的隐性基因奠定了理论基础。使用该参数，我们分析了6例α-1抗胰蛋白酶缺乏症患者，并以45例HapMap日本数据作为对照。虽然这6名患者来自日本不同地区，但我们可以从他们的基因分型数据中确定α1抗胰蛋白酶基因的位置。随着最近可用的1000k基因芯片的使用，我们能够识别生活在600年前的共同祖先的基因。该方法甚至适用于由多个基因引起的疾病，因此被认为是鉴定这些基因的有用方法。该方法已经批准了日本专利(4059517号)，目前正在转移到国际阶段。

The elucidation of the responsible gene for the multigene diseases is a difficult but an important subject. In this area, the whole genome association approach is frequently employed. However, the method is applicable only to diseases of which frequency is high, and the result often lacks reproducibility. We have invented the Homozygosity Fingerprinting method that targets multigene diseases. It is a non-parametric method applicable to recessive genes. We have determined several parameters for the method using Haldane's Poisson process model for the recombination of the chromosome, and established theoretical background for the identification of recessive genes that are derived from a small number of ancestors and now spread into the population. Using the parameter, we analyzed 6 patients with alpha-1 antitrypsin deficiency, with 45 HapMap Japanese data as a control. Although the 6 patients were from different areas of Japan, we could identify the location of alpha1-antitrypsin gene from their genotyping data. With the use of 1000k GeneChip recently available, we are able to identify genes derived from common ancestors who lived 600 years ago. The method is applicable even to the diseases that are caused by several genes, and thus is considered to be useful for the identification of such genes.The method has already approved Japanese patent (No. 4059517) and now being transferred to international phase.