在英国人群（英国糖尿病协会沃伦2号储存库）中进行的2型糖尿病易感基因座全基因组扫描：对573个家系的分析为1号染色体上的一个易感基因座提供了独立验证。
A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q.
作者信息
Wiltshire S, Hattersley A T, Hitman G A, Walker M, Levy J C, Sampson M, O'Rahilly S, Frayling T M, Bell J I, Lathrop G M, Bennett A, Dhillon R, Fletcher C, Groves C J, Jones E, Prestwich P, Simecek N, Rao P V, Wishart M, Bottazzo G F, Foxon R, Howell S, Smedley D, Cardon L R, Menzel S, McCarthy M I
机构信息
Imperial College Genetics and Genomics Research Institute & Division of Medicine, Imperial College, London, United Kingdom.
出版信息
Am J Hum Genet. 2001 Sep;69(3):553-69. doi: 10.1086/323249. Epub 2001 Aug 1.
Improved molecular understanding of the pathogenesis of type 2 diabetes is essential if current therapeutic and preventative options are to be extended. To identify diabetes-susceptibility genes, we have completed a primary (418-marker, 9-cM) autosomal-genome scan of 743 sib pairs (573 pedigrees) with type 2 diabetes who are from the Diabetes UK Warren 2 repository. Nonparametric linkage analysis of the entire data set identified seven regions showing evidence for linkage, with allele-sharing LOD scores > or =1.18 (P< or =.01). The strongest evidence was seen on chromosomes 8p21-22 (near D8S258 [LOD score 2.55]) and 10q23.3 (near D10S1765 [LOD score 1.99]), both coinciding with regions identified in previous scans in European subjects. This was also true of two lesser regions identified, on chromosomes 5q13 (D5S647 [LOD score 1.22] and 5q32 (D5S436 [LOD score 1.22]). Loci on 7p15.3 (LOD score 1.31) and 8q24.2 (LOD score 1.41) are novel. The final region showing evidence for linkage, on chromosome 1q24-25 (near D1S218 [LOD score 1.50]), colocalizes with evidence for linkage to diabetes found in Utah, French, and Pima families and in the GK rat. After dense-map genotyping (mean marker spacing 4.4 cM), evidence for linkage to this region increased to a LOD score of 1.98. Conditional analyses revealed nominally significant interactions between this locus and the regions on chromosomes 10q23.3 (P=.01) and 5q32 (P=.02). These data, derived from one of the largest genome scans undertaken in this condition, confirm that individual susceptibility-gene effects for type 2 diabetes are likely to be modest in size. Taken with genome scans in other populations, they provide both replication of previous evidence indicating the presence of a diabetes-susceptibility locus on chromosome 1q24-25 and support for the existence of additional loci on chromosomes 5, 8, and 10. These data should accelerate positional cloning efforts in these regions of interest.
如果要拓展当前的治疗和预防手段，深入了解2型糖尿病发病机制的分子层面知识至关重要。为了识别糖尿病易感基因，我们对来自英国糖尿病协会沃伦2号资料库的743对2型糖尿病同胞对（573个家系）进行了一次初步的（418个标记，9厘摩）常染色体基因组扫描。对整个数据集进行的非参数连锁分析确定了7个显示连锁证据的区域，等位基因共享LOD分数≥1.18（P≤0.01）。最强的证据出现在8号染色体p21 - 22区域（靠近D8S258，LOD分数为2.55）和10号染色体q23.3区域（靠近D10S1765，LOD分数为1.99），这两个区域都与之前在欧洲人群中扫描发现的区域重合。在5号染色体q13（D5S647，LOD分数为1.22）和5号染色体q32（D5S436，LOD分数为1.22）发现的两个较小区域也是如此。7号染色体p15.3区域（LOD分数为1.31）和8号染色体q24.2区域（LOD分数为1.41）是新发现的。最后一个显示连锁证据的区域在1号染色体q24 - 25区域（靠近D1S218，LOD分数为1.50），与在犹他州、法国和皮马族家系以及GK大鼠中发现的糖尿病连锁证据共定位。在进行密集图谱基因分型（平均标记间距4.4厘摩）后，与该区域连锁的证据增加到LOD分数为1.98。条件分析显示该位点与10号染色体q23.3区域（P = 0.01）和5号染色体q32区域（P = 0.02）之间存在名义上显著的相互作用。这些数据来自针对该疾病进行的最大规模基因组扫描之一，证实2型糖尿病个体易感基因的效应可能较小。与其他人群的基因组扫描结果相结合，它们既复制了之前表明1号染色体q24 - 25存在糖尿病易感位点的证据，也支持了5号、8号和10号染色体上存在其他位点的观点。这些数据应能加速在这些感兴趣区域的定位克隆工作。
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