Chromosomal mapping of a quantitative trait locus for the development of albuminuria in diabetic KK/Ta mice

The KK/Ta mouse strain serves as a suitable polygenic model for human type 2 diabetes. We previously reported a genome-wide linkage analysis of KK/Ta alleles contributing to type 2 diabetes and related phenotypes such as fasting hyperglycaemia, glucose intolerance, hyperinsulinaemia, obesity and dyslipidaemia.

Since KK/Ta mice spontaneously develop renal lesions closely resembling those in human diabetic nephropathy, we investigated the susceptibility loci using the KK/Ta x (BALB/c x KK/Ta) F1 backcross progeny in the present study.

A genome-wide analysis of susceptibility loci for albuminuria with microsatellite-based chromosomal maps showed a contributing KK/Ta locus, provisionally designated UA-1, with a significant linkage with the interval on chromosome 2 at 83.0 cM close to the microsatellite marker D2Mit311 with a maximum LOD of 3.5 (chi(2) = 13.2, P = 0.0003). UA-1 was different from the susceptibility loci contributing to type 2 diabetes, which we earlier identified. The mode of inheritance differed from that of hypertension. The progeny homozygous for UA-1 showed significantly higher urinary albumin levels.

Although there were no significant correlations between urinary albumin levels and other diabetic phenotypes, the group of progeny homozygous for both UA-1 and alleles for fasting hyperglycaemia showed the highest urinary albumin levels. Thus, UA-1 appears to increase the risk of diabetic nephropathy, particularly in individuals susceptible to fasting hyperglycaemia, in a gene dosage-dependent manner. There are potentially important candidate genes that may be relevant to diabetic nephropathy.