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鉴定和表征导致德国2型糖尿病（T2 DM）发生的序列变异。对394个患病同胞对（ASP）的全基因组扫描显示，在1号染色体（D1 S3669; NPL = 2.16; P = 0.003）和16号染色体（D16 S403; NPL = 2.305; P = 0.003）上有两个易感基因座。通过使用先进的多位点分析假设不同的遗传模型，我们确定了这两个位点之间的相互作用（LOD = 4.32）。在奥格斯堡家族三人组样本中对其他选定的候选基因进行基因分型。此外，我们收集了另外两个537和116个ASP（WÜDC）的复制样本，以及另外355个ASP（AUGC）。这些样本将用于精细绘图和基因座确认。然后，我们将阐明谁是负责连锁的家庭，在这两个，初始和复制样本。我们将在那些最有贡献的家庭中筛选链接区域内的所有可用SNP。然后将在维尔茨堡和奥格斯堡的所有可用ASP以及奥格斯堡的另外2，000例病例和4，000例对照中测试相关SNP（1，000例病例和2，000例对照尚未收集）。该策略应揭示对德国T2 DM发展具有功能重要性的序列变异。我们与Nancy J.考克斯在结合基因组扫描数据方面的国际合作将显着增加研究的力量。T2 DM变异体的鉴定和功能表征将有助于更好地理解糖尿病的分子基础。它将为预防和治疗的新方法提供科学基础，包括在临床疾病发作前识别高危受试者，以及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.