Type 1 Diabetes in the BB Rat: A Polygenic Disease
| Autor: | Philippe Poussier, Leili Marandi, Gary Y.C. Chao, Robert H. Wallis, Terri Ning, Janice Sarmiento, Eugene Hsieh, Kesheng Wang, Andrew D. Paterson |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
medicine.medical_specialty
Endocrinology Diabetes and Metabolism Genes MHC Class II Congenic 030209 endocrinology & metabolism Major histocompatibility complex Disease-Free Survival Major Histocompatibility Complex PTPN22 Mice 03 medical and health sciences 0302 clinical medicine Glycosuria Mice Inbred NOD Genetic linkage Commentaries Internal medicine Diabetes mellitus Genetics Internal Medicine medicine Animals Humans Rats Inbred BB Crosses Genetic 030304 developmental biology 0303 health sciences Type 1 diabetes Genome Models Genetic biology Haplotype Chromosome Mapping medicine.disease Rats 3. Good health Disease Models Animal Diabetes Mellitus Type 1 Endocrinology Commentary biology.protein Original Article Insulitis |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db08-1215 |
| Popis: | OBJECTIVE 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. RESEARCH DESIGN AND METHODS 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.BB1u.lyp) rats, where both Iddm1 and Iddm2 were fixed as BBDP. RESULTS 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. CONCLUSIONS 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. |
| Databáze: | OpenAIRE |
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