Identification of a critical interval for type 2 diabetes QTL on chromosome 4 in DDD-A^y mice

Type 2 diabetes mellitus (T2D) in male KK-A^y and B6-A^y mice is typically associated with hyperinsulinemia, whereas male DDD-A^y mice exhibit a marked decrease in circulating insulin levels due to the loss of pancreatic islet β-cells. T2D in male DDD-A^y mice is linked to Nidd/DDD, a significant quantitative trait locus (QTL) mapped with a 95% confidence interval (CI) between 112.44 and 151.47 Mbp on chromosome 4. Several T2D QTLs involving Nidd/SJL and Nidd/DBA have been identified on this chromosome; however, their allelic relationships remain unclear. In this study, two sets of male F₂-A^y mice produced by crossing C57BL/6J and DDD-A^y mice, and C3H/HeJ and DDD-A^y mice, were used to narrow the 95% CI of the Nidd/DDD to a 9.4 Mbp interval between 114.65 and 125.05 Mbp. Candidate genes underlying Nidd/DDD were identified, assuming that the causative variant is a nonsynonymous single nucleotide variant (nsSNV). The analysis identified 48 potential candidate nsSNVs unique to DDD-A^y mice compared to those in KK, B6, C3H, and DBA mice. Among these nsSNVs, 18 were identified in olfactory receptor genes, which have recently been implicated in the pathogenesis of T2D. The 9.4 Mbp region also contained Zfp69, a potential causative gene for Nidd/SJL, suggesting that Nidd/DDD could be allelic to Nidd/SJL but not to Nidd/DBA. In summary, the findings of this study provide insights into the allelic relationships between T2D QTLs on murine chromosome 4 and their underlying causative genetic variations.