Copy-number polymorphism analysis of type 2 diabetes gen

描述（由申请人提供）：最近使用各种技术进行的基因组研究表明，拷贝数多态性（CNP）在人类基因组中很常见，并且有CNP与复杂人类疾病相关的初步报告。在复杂疾病的连锁图谱研究中涉及的第一个区域之一是墨西哥裔美国人2型糖尿病（T2 D）染色体2 q37的NIDDM 1区域。类似地，在定位克隆研究的背景下被鉴定为T2 D易感性基因座的第一个基因是CAPN 10，在NIDDM 1区域中（Horikawa等人，2000年）。描述CAPN 10遗传变异与T2 D风险关系的模型很复杂。最初的报告确定了两种不同的3位点单倍型的组合，认为这是T2 D风险增加最大的因素。这些结果在一些研究中得到了重复，但许多研究未能重现最初报道的相关性。由于在CAPN 10的原始研究背景下进行的各种观察结果让人想起最近对CNP进行的观察，因此我们启动了一些初步研究，以评估CAPN 10含有传统基因分型和测序方法未检测到的CNP的可能性。这些初步研究的结果为CAPN 10中的CPN提供了足够令人信服的证据，我们提出了以下具体目标：1）检验CAPN 10含有用常规基因分型和测序方法未检测到的拷贝数多态性的假设，并设计可靠地表征这种CAPN 10多态性的方法; 2）检验CAPN 10的CNP与T2 D风险相关的假设; 3）使用合并模型调整现有模拟软件，以允许CNP能够检验替代统计方法，以帮助识别和表征CNP并检验与疾病的关联。

DESCRIPTION (provided by applicant): Recent genomic studies using a variety of techniques have revealed that copy number polymorphism (CNP) is common in the human genome, and there are preliminary reports of CNP associated with complex human diseases. One of the first regions implicated in linkage mapping studies of complex disorders was the NIDDM1 region of chromosome 2q37 in type 2 diabetes (T2D) in Mexican Americans. Similarly, the first gene identified as a susceptibility locus for T2D in the context of a positional cloning study was CAPN10, in the NIDDM1 region (Horikawa et al., 2000). The model characterizing the relationship of genetic variation at CAPN10 and the risk of T2D is complex. The original report identified a combination of two different 3-locus haplotypes as conferring the largest increase in risk for T2D. These results have been replicated in some studies, but many studies have not been able to reproduce the originally reported associations. Because a variety of observations made in the context of the original studies on CAPN10 are reminiscent of observations more recently made on CNP, we initiated some preliminary studies to assess the possibility that CAPN10 contains CNP that has not been detected with conventional genotyping and sequencing methods. Results of these preliminary studies provide sufficiently compelling evidence for CPN in CAPN10 that we propose the following specific aims: 1) Test the hypothesis that CAPN10 contains copy-number polymorphisms that have not been detected with conventional genotyping and sequencing methods and devise approaches for reliably characterizing such CAPN10 polymorphisms; 2) Test the hypothesis that CNP at CAPN10 is associated with risk of T2D; and 3) Adapt existing simulation software using coalescent models to allow for CNPs to enable tests of alternative statistical approaches to aid in identifying and characterizing CNP and testing associations with disease.