Identification of novel diabetes-related loci in a backcross of obese NZO with lean C3 H mice

Background: The identification of novel diabetes risk genes is an essential field for prevention and treatment of the disease. Mouse models represent useful tools to investigate diabetes-genetics factors associated to respective cellular function. In this project, a backcross between diabetes-susceptible New Zealand Obese (NZO) and lean C3HeB/FeJ mice was performed in order to identify potential new diabetes-inducing or -protective candidate genes.

Methods: The resulting N2 population from a backcross of NZO-C3HeB/FeJ mice was raised on a high-fat diet (45% fat/cal.) Diabetes-phenotypic traits as body weight, body composition, plasma glucose and insulin were weekly monitored. Mice genotype was determined using a genome-wide high-density SNP panel. Phenotype-genotype linkage analysis was performed using R/qtl software.

Results: Our linkage analysis led to identification of a major diabetes QTL (Quantitative Trait Locus) on chromosome 15 (13 cM, LOD 7.5). This locus was liked to blood glucose levels from week 7 to 21 (effect size: 100 mg/dl; NZO/NZO>C3 H/NZO). Furthermore, a suggestive QTL for body weight was observed from week 13 to 15 (32 cM, LOD 2.9; effect size: 2.7 g; NZO/NZO< C3 H/NZO). In addition, suggestive linkage with insulin levels was found at 21 weeks (34 cM, LOD 2.2; effect size: 2800 µg/ml; NZO/NZO< C3 H/NZO).

Conclusion: A major QTL was identified on Chr. 15 affecting diet-induced glucose levels already at early stages of life. The predicted function of underlying risk allele is presented by an islet dysfunction derived from obese NZO strain. Further experiments will focus on the identification and functional characterization of the responsible gene variants.