Molecular Analysis Of A Region On 1q Linked With Type 2

在先前对皮马印第安人2型糖尿病(T2 DM)易感基因的全基因组连锁扫描中，我们获得了与染色体1q21-q23上的标记连锁的最强有力的证据。随后，T2 DM的1Q连锁在几个不同的人群中被复制。我们搜索潜在的糖尿病易感基因(S)的策略基于两种互补的方法：1)密集分布的单核苷酸多态(SNPs)的系统分析；2)连锁区域内候选基因的变异/突变调查。到目前为止，已经/正在通过对糖尿病和非糖尿病PIMA的子集进行测序来分析100多个候选基因。信息性SNPs被测试与糖尿病的关联，并且它们对连锁的影响也被评估。最近，通过联合在1Q上发现T2 DM连锁的几个小组，建立了一个国际合作的1号染色体联盟，目的是促进对潜在糖尿病基因的搜索(S)。这项研究涉及对来自五个群体的5000多名受试者的分析(包括大约1000个PIMA)，到目前为止，这项工作已经导致了超过2000个SNPs的基因分型，在跨越大多数群体连锁高峰的13Mb的初始间隔内。 我们发现了几个与T2 DM有名义关联的区域，到目前为止，我们广泛分析了一个~200kb的区域，其中多个SNP与疾病酶有最强的关联，也可以解释大约25%的原始连锁。虽然我们检测到了许多变异，但这一策略无助于识别假定的致病变异。这一区域在人类和其他物种之间相当保守，因此可能需要一个实验动物模型(如基因敲除小鼠)来评估该区域变异的功能相关性。 由于13Mb区可能不包括致病突变(整个链接区超过30Mb长)，更多的SNPs已经(或正在)进行基因分型，以扩大分析区域。我们刚刚收到了另外1000个由该联盟进行基因分型的SNP，他们的分析正在进行中。这将为我们提供大约3500个SNP(包括在凤凰城进行基因分型的500多个SNP)，密度范围为每5-25kb一个SNP。我们预计，利用这些SNPs获得的结果将有助于确定可能含有糖尿病基因(S)的区域(S)的优先顺序，并将缩小关注区域，以便进一步进行彻底的分子遗传学分析。

In a previous genome-wide linkage scan for genes predisposing to type 2 diabetes mellitus (T2DM) in the Pima Indians, we obtained the strongest evidence for linkage with markers on chromosome 1q21-q23. Subsequently, the 1q linkage of T2DM has been replicated in several, diverse populations. Our strategy to search for the underlying diabetes susceptibility gene(s) has been based on two complementary approaches: 1) systematic analysis of densely spaced single nucleotide polymorphisms (SNPs); and 2) investigation of candidate genes within the linked region for variants/mutations. So far, over 100 candidate genes have been/are being analyzed by sequencing in a subset of diabetic and non-diabetic Pimas. Informative SNPs are tested for association with diabetes, and their effect on the linkage is also evaluated. More recently, an international collaborative Chromosome 1 Consortium has been established by uniting several of the groups which detected T2DM linkage on 1q, with the goal to facilitate search for the underlying diabetes gene(s). This startegy involves analysis of over 5000 subjects from five populations (including about 1000 Pimas), and so far this effort has led to genotyping of over 2000 SNPs within an initial interval of 13 Mb spanning the linkage peak in most populations. We found a few areas showing nominal association with T2DM and so far analyzed extensively a ~200 kilobase region in which multiple SNPs showed the strongest association with the disesase, and also could explain about 25% of the original linkage. Although we detected numerous variants, this strategy did not help to identify the putative causative variant. This area is fairly conserved between human and other species, and therefore an experimental animal model (such as knockout mice) may be needed to assess the functional relevance of the variants in this region. As the 13 Mb region may not include the causative mutation (the whole linked region is over 30 Mb long), more SNPs has been (or are being) genotyped to expand the analyzed region. We just received an additional 1000 SNPs genotyped by the Consortium and their analysis is in progress. This will provide us with approximately 3500 SNPs (including over 500 SNPs that were genotyped here in Phoenix), giving a density range of one SNP per every 5-25 kb. We anticipate that the results obtained with these SNPs will help to prioritize region(s) which are likely to harbor the diabetes gene(s), and will narrow down the area of interest for further thorough molecular genetic analysis.