Characterization of a C3 H-specific diabetes-suppressor on chromosome 15

 

Aim:

To identify new diabetes-associated genes we investigated an outcross population generated by crossbreeding of diabetes-susceptible New Zealand Obese (NZO) mice with the diabetes-resistant C3HeB/FeJ mouse strain.

Methods:

We measured diabetes-related traits in a (NZOxC3 H)NZO backcross population of 300 males fed a high-fat-diet (45% fat/cal.) Linkage analysis was performed by in silico calculation of phenotype-genotype associations. Differential gene expression between the parental strains was analyzed by qPCR.

Results:

We identified a major QTL (Quantitative Trait Locus) for blood glucose on chromosome 15 (13 cM, LOD 7.5). Mice carrying the protective C3 H allele had significantly reduced blood glucose levels compared to NZO allele carriers (size effect at week 15: 100 mg/dl). This effect was shown to be independent of the body weight of the animals. Moreover, mean diabetes prevalence at week 15 for Chr15/NZO allele carriers was 76% compared to 53% for Chr.15/C3 H alleles carriers. Similar results were observed for diabetes mortality, 16% and 6% at week 15, and 33% and 12% at week 21. This phenotype was reconstituted in a recombinant congenic (RCS) mouse line carrying the critical region of Chr.15 from C3 H on a NZO background. Expression profiling revealed approximately 15 candidate genes in the locus differentially expressed in WAT, BAT, liver, pancreas and skeletal muscle.

Conclusion:

A major QTL was found on Chr. 15 triggering diabetes development already at early stages of life. We hypothesize that the C3 H allele confers diabetes protection by improving islet function and survival in NZO mice.