Type 1 diabetes in the BB rat: a polygenic disease

Area of Science:

• Genetics and Genomics
• Immunology
• Endocrinology

Background:

• Type 1 diabetes susceptibility in Biobreeding diabetes-prone (BBDP) rats is primarily attributed to the major histocompatibility complex (MHC) class II (Iddm1) and Gimap5 (Iddm2) loci.
• The significant impact of these known loci has previously hindered the identification of additional genetic contributors to type 1 diabetes in this model.

Purpose of the Study:

• To investigate the hypothesis that type 1 diabetes in BBDP rats is a polygenic trait.
• To conduct a comprehensive genome-wide linkage analysis to identify novel susceptibility loci for type 1 diabetes and related subphenotypes.

Main Methods:

• Genome-wide linkage analysis was performed on 574 F2 animals derived from a cross-intercross between BBDP rats and double congenic ACI.BBDP-RT1u,Gimap5 rats.
• Analysis focused on type 1 diabetes, age of disease onset (AOO), and insulitis severity, with Iddm1 and Iddm2 fixed in the congenic line.

Main Results:

• Eight type 1 diabetes susceptibility loci were mapped, with six showing significant linkage (chromosomes 1, 3, 6 [two loci], 12, 14) and two suggestive linkage (chromosomes 2, 17).
• Several loci were also linked to insulitis severity and islet atrophy, while four loci showed suggestive linkage to AOO.
• Genes associated with human type 1 diabetes, including INS, PTPN22, IL2/IL21, C1QTNF6, and C12orf30, are located within identified linkage regions.

Conclusions:

• The BBDP diabetic syndrome is confirmed as a complex, polygenic disease.
• This research indicates potential shared genetic susceptibility factors between BBDP rat type 1 diabetes and human type 1 diabetes, extending beyond the MHC class II locus.