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PMID: 19168599 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Type 1 diabetes in the BB rat: a polygenic disease.

Diabetes ·Vol. 58 ·No. 4 ·2009-04-00 ·Pages 1007-17

Wallis RH, Wang K, Marandi L, Hsieh E, Ning T, Chao GY, Sarmiento J, Paterson AD, Poussier P

Abstract

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.

MeSH Terms
Animals Chromosome Mapping Crosses, Genetic Diabetes Mellitus, Type 1/genetics Disease Models, Animal Disease-Free Survival Genome Glycosuria Humans Models, Genetic Rats Rats, Inbred BB/genetics
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Wallis Robert H
Sunnybrook Health Sciences Centre Research Institute, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Wang KeSheng
Marandi Leili
Hsieh Eugene
Ning Terri
Chao Gary Y C
Sarmiento Janice
Paterson Andrew D
Poussier Philippe
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Article Info
Journal
Diabetes
Abbr.
Diabetes
ISSN
1939-327X
DOI
10.2337/db08-1215
Published
2009-04-00
Epub
2009-00-23
Pages
1007-17
Language
English
Region
United States
NLM ID
0372763
PMCID
PMC2661594
Subset
IM
Corrections
CommentIn
PMID: 19336688
External Links
PubMed source DOI: 10.2337/db08-1215 PMC Full Text View journal details
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