Osterholm A-M, He B, Pitkaniemi J, Albinsson L, Berg T, Sarti C, Tuomilehto J, Tryggvason K
Department of Medical Biochemistry and Biophysics, Division of Matrix Biology, Karolinska Institutet, Stockholm, Sweden.
Kidney Int. 2007 Jan;71(2):140-5. doi: 10.1038/sj.ki.5001933. Epub 2006 Oct 4.
Diabetic nephropathy (DN) is the primary cause of morbidity and mortality in patients with type 1 as well as type 2 diabetes, and accounts for 40% of end-stage renal disease in the Western world. Familial clustering of DN suggests importance of genetic factors in the development of the disease. In the present study, we performed a two-stage genome-wide scan to search for chromosomal loci containing susceptibility genes for nephropathy in patients with type 1 diabetes. In total, 83 discordant sib pairs (DSPs), sibs concordant for type 1 diabetes but discordant for nephropathy, were collected from Finland, a homogeneous population with one of the highest incidences of type 1 diabetes. To map loci for DN, we applied DSP analysis to detect linkage. In the initial scan, 73 DSPs were typed using 900 markers with an average intermarker distance of approximately 4 cM. Multipoint DSP analysis identified five chromosome regions (3q, 4p, 9q, 16q, and 22p) with maximum logarithm of odds (LOD) score (MLS) >or=1.0 (corresponding to a nominal P-value <or=0.015). In the second stage, additional 43 markers flanking these five loci were genotyped in all 83 DSPs. Using simulations, we determined the empirical threshold with LOD score of 1.76 and 3.12 for suggestive and significant linkage, respectively. No locus reached the genome-wide significance of 5%. However, one locus on 3q reached suggestive linkage with MLS of 2.67 (P=4.4 x 10(-4)). These results, together with data from others, suggest that the locus on 3q most likely has a susceptibility gene for DN.
糖尿病肾病（DN）是1型和2型糖尿病患者发病和死亡的主要原因，在西方世界占终末期肾病的40%。DN的家族聚集性表明遗传因素在该疾病发生过程中具有重要作用。在本研究中，我们进行了两阶段全基因组扫描，以寻找1型糖尿病患者中包含肾病易感基因的染色体位点。总共从芬兰收集了83对不一致同胞对（DSPs），这些同胞对1型糖尿病一致但肾病不一致，芬兰是1型糖尿病发病率最高的同质人群之一。为了定位DN的位点，我们应用DSP分析来检测连锁。在初始扫描中，使用900个标记对73对DSPs进行分型，标记间平均距离约为4厘摩。多点DSP分析确定了五个染色体区域（3q、4p、9q、16q和22p），最大对数优势（LOD）得分（MLS）≥1.0（对应名义P值≤0.015）。在第二阶段，对这五个位点两侧的另外43个标记在所有83对DSPs中进行基因分型。通过模拟，我们分别确定了提示性连锁和显著连锁的经验阈值，LOD得分分别为1.76和3.12。没有位点达到全基因组显著性水平5%。然而，3q上的一个位点达到提示性连锁，MLS为2.67（P = 4.4×10⁻⁴）。这些结果与其他研究数据一起表明，3q上的位点很可能具有DN的易感基因。
