A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene
A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene
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DOI：
10.1038/nature06010
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发表时间：
2007-08-02
期刊：
影响因子：
64.8
通讯作者：
Polychronakos, Constantin
中科院分区：
文献类型：
--
作者：
Hakonarson, Hakon;Grant, Struan F. A.;Polychronakos, Constantin
儿童中1型糖尿病（T1D）是由于胰腺β细胞自身免疫性破坏而导致胰岛素产生不足的原因（1）。 T1D的许多遗传决定因素已经通过候选基因研究建立，主要是在主要的组织相容性复合物（2-4）内，也可以在其他基因座（5-12）内建立。为了确定增加T1D风险的新遗传因素，我们在大量的欧洲血统中进行了全基因组关联研究。除了确认先前确定的基因座（2-9）外，我们还发现T1D与16p13染色体上的233-KB连杆不平衡块内的变化显着相关。该区域包含KIAA0350，该区域的基因产物预测为糖结合c型凝集素。强链接不平衡的三种基因（rs2903692，rs725613和rs17673553）的三种常见非编码变体达到了与T1D相关的基因组的重要性。随后在独立队列中进行的传播不平衡测试复制研究证实了该关联。这些结果表明，KIAA0350可能与T1D的发病机理有关，并证明了全基因组关联方法在鉴定复杂性状的先前未引起的遗传决定因素时的实用性。
Type 1 diabetes (T1D) in children results from autoimmune destruction of pancreatic beta cells, leading to insufficient production of insulin(1). A number of genetic determinants of T1D have already been established through candidate gene studies, primarily within the major histocompatibility complex(2-4) but also within other loci(5-12). To identify new genetic factors that increase the risk of T1D, we performed a genome-wide association study in a large paediatric cohort of European descent. In addition to confirming previously identified loci(2-9), we found that T1D was significantly associated with variation within a 233-kb linkage disequilibrium block on chromosome 16p13. This region contains KIAA0350, the gene product of which is predicted to be a sugar-binding, C-type lectin. Three common non-coding variants of the gene (rs2903692, rs725613 and rs17673553) in strong linkage disequilibrium reached genome-wide significance for association with T1D. A subsequent transmission disequilibrium test replication study in an independent cohort confirmed the association. These results indicate that KIAA0350 might be involved in the pathogenesis of T1D and demonstrate the utility of the genome-wide association approach in the identification of previously unsuspected genetic determinants of complex traits.