Wallis Robert H, Wang KeSheng, Marandi Leili, Hsieh Eugene, Ning Terri, Chao Gary Y C, Sarmiento Janice, Paterson Andrew D, Poussier Philippe
Sunnybrook Health Sciences Centre Research Institute, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Diabetes. 2009 Apr;58(4):1007-17. doi: 10.2337/db08-1215. Epub 2009 Jan 23.
Two type 1 diabetes susceptibility genes have been identified in the spontaneously diabetic biobreeding diabetes-prone (BBDP) rat, the major histocompatibility complex (MHC) (RT1) class II u haplotype (Iddm1) and Gimap5 (Iddm2). The strong effects of these have impeded previous efforts to map additional loci. We tested the hypothesis that type 1 diabetes is a polygenic disease in the BBDP rat.
We performed the most comprehensive genome-wide linkage analysis for type 1 diabetes, age of disease onset (AOO), and insulitis subphenotypes in 574 F2 animals from a cross-intercross between BBDP and type 1 diabetes-resistant, double congenic ACI.BBDP-RT1u,Gimap5 (ACI.BB(1u.lyp)) rats, where both Iddm1 and Iddm2 were fixed as BBDP.
A total of 19% of these F2 animals developed type 1 diabetes, and eight type 1 diabetes susceptibility loci were mapped, six showing significant linkage (chromosomes 1, 3, 6 [two loci], 12, and 14) and two (chromosomes 2 and 17) suggestive linkage. The chromosomes 6, 12, and 14 intervals were also linked to the severity of islet infiltration by immunocytes, while those on chromosomes 1, 6 (two loci), 14, 17, and a type 1 diabetes-unlinked chromosome 8 interval showed significant linkage to the degree of islet atrophy. Four loci exhibited suggestive linkage to AOO on chromosomes 2 (two loci), 7, and 18 but were unlinked to type 1 diabetes. INS, PTPN22, IL2/IL21, C1QTNF6, and C12orf30, associated with human type 1 diabetes, are contained within the chromosomes 1, 2, 7, and 12 loci.
This study demonstrates that the BBDP diabetic syndrome is a complex, polygenic disease that may share additional susceptibility genes besides MHC class II with human type 1 diabetes.
在自发性糖尿病的生物繁殖糖尿病易感性（BBDP）大鼠中已鉴定出两个1型糖尿病易感基因，即主要组织相容性复合体（MHC）（RT1）II类u单倍型（Iddm1）和Gimap5（Iddm2）。它们的强大作用阻碍了先前定位其他基因座的努力。我们检验了1型糖尿病在BBDP大鼠中是一种多基因疾病的假设。
我们对574只F2动物进行了最全面的全基因组连锁分析，这些动物来自BBDP与1型糖尿病抗性双基因同源ACI.BBDP-RT1u，Gimap5（ACI.BB(1u.lyp)）大鼠之间的杂交-回交，其中Iddm1和Iddm2均固定为BBDP型。
这些F2动物中共有19%发生了1型糖尿病，定位了8个1型糖尿病易感基因座，6个显示出显著连锁（染色体1、3、6[两个基因座]、12和14），两个（染色体2和17）显示出可能连锁。染色体6、12和14区间也与免疫细胞对胰岛的浸润严重程度相关，而染色体1、6（两个基因座）、14、17上的区间以及一个与1型糖尿病不连锁的染色体8区间与胰岛萎缩程度显示出显著连锁。四个基因座在染色体2（两个基因座）、7和18上显示出与疾病发病年龄（AOO）的可能连锁，但与1型糖尿病不连锁。与人类1型糖尿病相关的INS、PTPN22、IL2/IL21、C1QTNF6和C12orf30包含在染色体1、2、7和12基因座内。
本研究表明，BBDP糖尿病综合征是一种复杂的多基因疾病，除了MHC II类基因外，可能还与人类1型糖尿病共享其他易感基因。
