Rentapping the insulin gene/IDDM2 locus in type 1 diabetes
Rentapping the insulin gene/IDDM2 locus in type 1 diabetes
复制标题
DOI：
10.2337/diabetes.53.7.1884
复制
发表时间：
2004-07-01
期刊：
影响因子：
7.7
通讯作者：
Todd, JA
中科院分区：
文献类型：
--
作者：
Barratt, BJ;Payne, F;Todd, JA
IDDM 2基因座的1型糖尿病易感性先前被定位于胰岛素基因（INS）5'端的可变数目串联重复序列（VNTR）。然而，观察相关标记以外的4.1 kb的间隔，以前被认为是定义IDDM 2协会的限制，提出了可能性，VNTR协会可能导致连锁不平衡（LD）与未知的多态性。因此，我们确定了总共177个多态性，并获得了其中75个在多达434个家系的基因型。我们发现，虽然疾病易感性确实映射到4.1 kb区域内，但除了VNTR之外，还有两个同样可能的致病变异体候选者，-23HphI和+1140 A/C。在2,960个家系中的进一步分析不支持VNTR谱系之间的关联差异，这使得先前能够排除这两种多态性。因此，我们不能排除-23HphI和+1140A/C具有病因学影响。我们的映射结果使用强大的回归方法显示如何精确地映射一种常见疾病的变异，即使在一个区域内的强LD，特别是IDDM 2映射到一个或多个三个常见的变异在一个类似的to 2-kb区域的染色体11 p15。
Type 1 diabetes susceptibility at the IDDM2 locus was previously mapped to a variable number tandem repeat (VNTR) 5' of the insulin gene (INS). However, the observation of associated markers outside a 4.1-kb interval, previously considered to define the limits of IDDM2 association, raised the possibility that the VNTR association might result from linkage disequilibrium (LD) with an unknown polymorphism. We therefore identified a total of 177 polymorphisms and obtained genotypes for 75 of these in up to 434 pedigrees. We found that, whereas disease susceptibility did map to within the 4.1-kb region, there were two equally likely candidates for the causal variant, -23HphI and + 1140A/C, in addition to the VNTR. Further analyses in 2,960 pedigrees did not support the difference in association between VNTR lineages that had previously enabled the exclusion of these two polymorphisms. Therefore, we were unable to rule out -23HphI and +1140A/C having an etiological effect. Our mapping results using robust regression methods show how precisely a variant for a common disease can be mapped, even within a region of strong LD, and specifically that IDDM2 maps to one or more of three common variants in a similar to2-kb region of chromosome 11p15.