Molecular genetics of type 2 diabetes (T2DM) in Germany: Genes / Polymorphisms for T2DM - Cloning of diabetes susceptibility sequence variants

该项目的总体目标是识别和表征导致德国2型糖尿病(T2 DM)发病的序列变异。全基因组扫描发现1号染色体(D1S3669；Np1=2.16；P=0.003)和16号染色体(D16S403；Np1=2.305；P=0.003)上有两个易感基因座。通过使用假设不同遗传模式的高级多位点分析，我们确定了这两个座位之间的交互作用(LOD=4.32)。其他选定的候选基因在奥格斯堡家族三人组样本中进行了基因分型。此外，我们还收集了另外两个复制样本，即537和116个ASP(WÜDC)，以及另外355个ASP(AUGC)。这些样本将用于完成作图和位置确认。然后，我们将阐明在初始样本和复制样本中负责连锁的家族。我们将在那些贡献最大的家庭中筛选链接地区内的所有可用的SNP。随后将在维尔茨堡和奥格斯堡的所有可用的ASP以及奥格斯堡的另外2,000个病例和4,000个对照(尚待收集的1,000个病例和2,000个对照)中检测相关的SNPs。这一策略应该揭示序列变异，这些变异对德国T2 DM的发展具有重要的功能。我们与南希·J·考克斯在结合基因组扫描数据方面的国际合作将极大地增强这项研究的力量。T2 DM变异体的鉴定和功能鉴定将有助于更好地了解糖尿病的分子基础。它将为新的预防和治疗方法提供科学基础，包括在临床疾病发生之前确定高危对象，并根据潜在分子缺陷的性质确定具体的治疗方式。

The overall aim of this project is to identify and characterize sequence variants that contribute to the development of type 2 diabetes mellitus (T2DM) in Germany. A total genome scan in 394 affected sib pairs (ASP) revealed two susceptibility loci on chromosomes 1 (D1S3669; NPL = 2.16; P = 0.003) and 16 (D16S403; NPL = 2.305; P = 0.003). By using advanced multilocus analyses assuming different inheritance models we identified an interaction between those two loci (LOD = 4.32). Other selected candidate genes were genotyped in the Augsburg family trio sample. Further, we collected two additional replication samples of 537 and 116 ASPs (WÜDC), and another 355 ASPs (AUGC). Those samples will be used for finemapping and locus confirmation. Then we will elucidate the families who were responsible for linkage in both, the initial and the replication samples. We will screen all available SNPs within the linked regions in those most contributing families. Associated SNPs will then be tested in all available ASPs from Würzburg and Augsburg as well as in another 2,000 cases and 4,000 controls from Augsburg (1,000 cases and 2,000 controls yet to be collected). This strategy should reveal sequence variants which are of functional importance for the development of T2DM in Germany. Our international collaborations with Nancy J. Cox in terms of combining genome-scan data will significantly increase the power of the study. The identification and functional characterization of the variants for T2DM will lead to a better understanding of the molecular basis of diabetes mellitus. It will provide the scientific foundation for new approaches for prevention and treatment including the identification of atrisk subjects before the onset of clinical disease and specific treatment modalities based on the nature of the underlying molecular defect.