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（T2DM）发展的序列变异。对394对患病兄弟姐妹（ASP）进行全基因组扫描，发现1号染色体（D1S3669; NPL = 2.16; P = 0.003）和16号染色体（D16S403; NPL = 2.305; P = 0.003）上有两个易感位点。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）。其他选择的候选基因在奥格斯堡家族三重奏样本中进行基因分型。此外，我们还收集了两个额外的537和116个asp的复制样本（WÜDC），以及另外355个asp （AUGC）。这些样本将用于精细定位和基因座确认。然后，我们将阐明在初始和复制样本中负责连锁的家庭。我们将在那些贡献最多的家庭的相关区域中筛选所有可用的snp。然后将对来自w<s:1> rzburg和Augsburg的所有可用asp以及来自Augsburg的另外2,000例病例和4,000例对照进行相关snp检测（1,000例病例和2,000例对照有待收集）。该策略应揭示对德国T2DM发展具有重要功能的序列变异。我们与Nancy J. Cox在结合基因组扫描数据方面的国际合作将显著增加研究的力量。2型糖尿病变异的鉴定和功能特征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，包括在临床疾病发病前识别风险主体和基于潜在分子缺陷性质的特定治疗方式。

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.