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

描述（由申请人提供）：最近使用各种技术的基因组研究表明，拷贝数多态性（CNP）在人类基因组中很常见，并且有初步报道称CNP与复杂的人类疾病有关。在复杂疾病连锁图谱研究中涉及的第一个区域是墨西哥裔美国人2型糖尿病（T2D）染色体2q37的NIDDM1区域。同样，在定位克隆研究中，第一个被确定为T2D易感性位点的基因是位于NIDDM1区域的CAPN10 （Horikawa et al., 2000）。表征CAPN10基因变异与T2D风险关系的模型是复杂的。最初的报告确定了两种不同的3位点单倍型的组合，使T2D的风险增加最多。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关联。由于在CAPN10的原始研究背景下所做的各种观察让人想起最近在CNP上所做的观察，我们启动了一些初步研究，以评估CAPN10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CAPN10中的CPN提供了充分有力的证据，我们提出了以下具体目标：1)验证CAPN10包含拷贝数多态性的假设，这些多态性是传统基因分型和测序方法无法检测到的，并设计出可靠表征CAPN10多态性的方法；2)检验CAPN10的CNP与T2D风险相关的假设；3)使用聚结模型调整现有的模拟软件，使CNP能够进行替代统计方法的测试，以帮助识别和表征CNP并测试与疾病的关联。

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.