Identification of T1D susceptibility genes within the MHC region by combining protein interaction networks and SNP genotyping data.
Identification of T1D susceptibility genes within the MHC region by combining protein interaction networks and SNP genotyping data.
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DOI：
10.1111/j.1463-1326.2008.01004.x
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发表时间：
2009-02
期刊：
影响因子：
--
通讯作者：
Diabetes Genetics Consortium
中科院分区：
文献类型：
--
作者：
Brorsson C;Hansen NT;Lage K;Bergholdt R;Brunak S;Pociot F;Diabetes Genetics Consortium
目的：开发新的方法，在6号染色体上的主要组织相容性复合体(MHC)区域内，独立于人类白细胞抗原(HLA)-DRB1、-DQA1、-DQB1基因之间的已知连锁不平衡(LD)，识别与1型糖尿病发病风险相关的新基因。我们开发了一种新的方法，将单核苷酸多态(SNP)基因分型数据与蛋白质-蛋白质相互作用(PPI)网络相结合，以识别从MHC区域编码的蛋白质丰富的疾病相关网络模块。对1型糖尿病遗传联盟(T1DGC)产生的1000个受影响的后代三人中约2500个位于4Mb MHC区域的SNPs进行了分析。选择每个基因中关联最多的SNP，并将基因映射到PPI网络以识别相互作用伙伴。使用排列对关联测试和所产生的相互作用蛋白质模块进行统计评估。共有151个基因可以被定位到蛋白质相互作用网络中的节点，并确定了它们的相互作用伙伴。使用这种方法，五个蛋白质相互作用模块达到了统计学意义。已识别的蛋白质在T1D的发病机制中是众所周知的，但这些模块还包含与β细胞发育和糖尿病并发症有关的其他候选蛋白质。MHC区域内广泛的LD使得开发新的方法来分析基因分型数据以识别T1D的其他危险基因是重要的。将遗传数据与功能通路的知识相结合，为T1D的潜在机制提供了新的见解。
To develop novel methods for identifying new genes that contribute to the risk of developing type 1 diabetes within the Major Histocompatibility Complex (MHC) region on chromosome 6, independently of the known linkage disequilibrium (LD) between human leucocyte antigen (HLA)-DRB1, -DQA1, -DQB1 genes. We have developed a novel method that combines single nucleotide polymorphism (SNP) genotyping data with protein–protein interaction (ppi) networks to identify disease-associated network modules enriched for proteins encoded from the MHC region. Approximately 2500 SNPs located in the 4 Mb MHC region were analysed in 1000 affected offspring trios generated by the Type 1 Diabetes Genetics Consortium (T1DGC). The most associated SNP in each gene was chosen and genes were mapped to ppi networks for identification of interaction partners. The association testing and resulting interacting protein modules were statistically evaluated using permutation. A total of 151 genes could be mapped to nodes within the protein interaction network and their interaction partners were identified. Five protein interaction modules reached statistical significance using this approach. The identified proteins are well known in the pathogenesis of T1D, but the modules also contain additional candidates that have been implicated in β-cell development and diabetic complications. The extensive LD within the MHC region makes it important to develop new methods for analysing genotyping data for identification of additional risk genes for T1D. Combining genetic data with knowledge about functional pathways provides new insight into mechanisms underlying T1D.
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影响因子：
8.2
作者：
Lindholm, E.;Bakhtadze, E.;Agardh, C. -D.
通讯作者：
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影响因子：
5.8
作者：
ITOH, N;HANAFUSA, T;TARUI, S
通讯作者：
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影响因子：
3.5
作者：
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通讯作者：
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DOI：
10.1073/pnas.91.12.5710
发表时间：
1994-06-07
影响因子：
11.1
作者：
SMITH, MA;TANEDA, S;PERRY, G
通讯作者：
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影响因子：
15.8
作者：
Steer, SA;Scarim, AL;Chambers, KT;Corbett, JA
通讯作者：
Corbett, JA