High-density single nucleotide polymorphism genome-wide linkage scan for susceptibility genes for diabetic nephropathy in type 1 diabetes: discordant sibpair approach.
High-density single nucleotide polymorphism genome-wide linkage scan for susceptibility genes for diabetic nephropathy in type 1 diabetes: discordant sibpair approach.
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DOI：
10.2337/db07-1086
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发表时间：
2008-09
期刊：
影响因子：
7.7
通讯作者：
Krolewski, Andrzej S.
中科院分区：
文献类型：
--
作者：
Rogus, John J.;Poznik, G. David;Pezzolesi, Marcus G.;Smiles, Adam M.;Dunn, Jonathon;Walker, William;Wanic, Krzysztof;Moczulski, Dariusz;Canani, Luis;Araki, Shinichi;Makita, Yuichiro;Warram, James H.;Krolewski, Andrzej S.
目的-流行病学和家族研究表明，易感基因在糖尿病肾病（定义为1型糖尿病持续性蛋白尿或终末期肾病（ESRD））的病因学中起重要作用。研究设计和方法-为了有效地寻找携带糖尿病肾病基因的基因组区域，我们对100对与1型糖尿病一致但与糖尿病肾病不一致的同胞进行了5，382个信息单核苷酸多态性扫描。除了检测与糖尿病肾病的联系外，该设计还允许通过传统的受累同胞（ASP）分析进行1型糖尿病的联系分析。在权衡连锁证据时，我们考虑了最大对数的优势得分（最大似然得分[MLS]）值和相应的等位基因共享模式，使用软件包SPLAT计算和图形化查看。结果：我们对糖尿病肾病的主要发现，广义上说，是在染色体19 q（MLS = 3.1），第二个峰存在于染色体2 q（MLS = 2.1）。根据疾病是否进展为ESRD对不一致的同胞进行分层，提示染色体1 q（仅ESRD）、染色体20 p（仅蛋白尿）和染色体3q（两个相距58 cm的位点，一个仅ESRD，另一个仅蛋白尿）上有四个三级峰。此外，对130例1型糖尿病ASP的分析证实了与染色体6p上的HLA区域（MLS = 9.2）和染色体6 q上的IDM 15（MLS = 3.1）的连锁。结论：本研究确定了几个新的基因位点作为糖尿病肾病的候选基因，没有一个是1型糖尿病肾病的唯一遗传决定因素。此外，这项研究证实了两个先前报道的1型糖尿病位点。
OBJECTIVE— Epidemiological and family studies have demonstrated that susceptibility genes play an important role in the etiology of diabetic nephropathy, defined as persistent proteinuria or end-stage renal disease (ESRD) in type 1 diabetes. RESEARCH DESIGN AND METHODS— To efficiently search for genomic regions harboring diabetic nephropathy genes, we conducted a scan using 5,382 informative single nucleotide polymorphisms on 100 sibpairs concordant for type 1 diabetes but discordant for diabetic nephropathy. In addition to being powerful for detecting linkage to diabetic nephropathy, this design allows linkage analysis on type 1 diabetes via traditional affected sibpair (ASP) analysis. In weighing the evidence for linkage, we considered maximum logarithm of odds score (maximum likelihood score [MLS]) values and corresponding allelic sharing patterns, calculated and viewed graphically using the software package SPLAT. RESULTS— Our primary finding for diabetic nephropathy, broadly defined, is on chromosome 19q (MLS = 3.1), and a secondary peak exists on chromosome 2q (MLS = 2.1). Stratification of discordant sibpairs based on whether disease had progressed to ESRD suggested four tertiary peaks on chromosome 1q (ESRD only), chromosome 20p (proteinuria only), and chromosome 3q (two loci 58 cm apart, one for ESRD only and another for proteinuria only). Additionally, analysis of 130 ASPs for type 1 diabetes confirmed the linkage to the HLA region on chromosome 6p (MLS = 9.2) and IDDM15 on chromosome 6q (MLS = 3.1). CONCLUSIONS— This study identified several novel loci as candidates for diabetic nephropathy, none of which appear to be the sole genetic determinant of diabetic nephropathy in type 1 diabetes. In addition, this study confirms two previously reported type 1 diabetes loci.
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