POSITIONAL CLONING OF A DIABETES GENE ON CHROMOSOME 11

我们之前已经在11q23-24上发现了一个与体重指数(LOD=3.6)、年龄调整的糖尿病(LOD=1.7)和糖尿病的联合表型(LOD=5.2)相关联的区域。我们对另外3,000名被选为BMI但不一定来自糖尿病信息家系的人进行了该区域内10个标记的基因分型。在第二组PIMA中，与BMI没有关联，这表明最初的关联依赖于BMI和糖尿病之间的相互作用。对11q22-24区域的所有已知候选基因，包括Apo CIII/AIV/A2基因簇、两个内向整流钾通道和多巴胺受体DRD2，通过对每个基因中的几个单核苷酸多态性(SNPs)进行基因分型。DRD2中的几个SNPs与体重指数显著相关；因此，对该基因进行了全序列测定，并对1300个PIMA中的两个SNPs进行了基因分型。不幸的是，在DRD2中检测到的SNPs似乎不会导致在该区域观察到的BMI的连锁。我们还通过在Chrom 11q上的连锁区域识别重叠的YAC克隆，创建了一个物理图谱。我们目前正在这一地区构建一个BAC重叠群。在每个BAC上都发现了SNP，然后在200个信息性同胞对的DNA上进行了基因分型。-位置克隆、单核苷酸多态、遗传图谱-人类受试者

We have previously identified a region of linkage to both body mass index (LOD=3.6), age-adjusted diabetes (LOD=1.7) and the combined phenotype of diabesity (LOD=5.2)on chrom 11q23-24. We genotyped 10 markers within this region on 3,000 additional individuals who were selected for BMI, but were not necessarily from families informative for diabetes. There was no linkage to BMI in this second set of Pimas, indicating that the initial linkage was dependent upon an interaction between BMI and diabetes. All known candidate genes in the region from 11q22-24, including the Apo CIII/AIV/A2 gene cluster, two inwardly rectifying potassium channels, and the dopamine receptor DRD2 were analyzed by genotyping several single nucleotide polymorphisms (SNPs)in each gene. Several SNPs in DRD2 showed a significant association with BMI; therefore, this gene was sequenced in its entirety and two SNPs were genotyped in 1300 Pimas. Unfortunately, SNPs detected in DRD2 do not appear to result in the linkage to BMI observed in this region. We have also created a physical map by identifying overlapping YAC clones across the region of linkage on chrom 11q. We are currently contructing a BAC contig across this region. SNPs are being identified on each of the BACs and are then being genotyped on DNAs from 200 informative sibpairs. - positional cloning, single nucleotide polymorphisms, genetic mapping - Human Subjects