Copy-number polymorphism analysis of the type 2 diabetes gene calpain 10

描述(申请人提供)：最近使用各种技术的基因组研究表明，拷贝数多态(CNP)在人类基因组中很常见，并且有与复杂人类疾病相关的CNP的初步报告。在墨西哥裔美国人中，复杂疾病的连锁图谱研究涉及的第一个区域之一是染色体2q37的NIDDM1区域。同样，在定位克隆研究的背景下，第一个被确定为T2D易感基因的基因是NIDDM1区域的CAPN10(Horikawa等人，2000年)。描述CAPN10基因变异与T2D风险之间关系的模型是复杂的。最初的报告发现，两种不同的3位点单倍型的组合导致了T2D风险的最大增加。这些结果在一些研究中得到了复制，但许多研究未能再现最初报道的相关性。由于在最初对CAPN10的研究中所做的各种观察结果与最近对CNP所做的观察结果相类似，我们启动了一些初步研究，以评估CAPN10含有常规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CPN在CAPN10中的作用提供了足够令人信服的证据，因此我们提出了以下具体目标：1)测试CAPN10包含传统基因分型和测序方法未检测到的拷贝数多态的假设，并设计出可靠地表征此类CAPN10多态的方法；2)测试CAPN10处的CNP与T2D风险相关的假设；以及3)使用合并模型调整现有的模拟软件，以允许CNP能够进行替代统计方法的测试，以帮助识别和表征CNP以及测试与疾病的关联。

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.