Experiment
Linkage analysis was performed on 208 male animals from a KK/Ta x (BALB/c x KK/Ta)F1 backross to identify loci associated with urinary albuminuria. Parental strain KK/Ta is a mouse model of type 2 diabetes as these animals spontaneously develop fasting hyperglycemia, glucose intolerance, hyperinsulinemia, mild obesity, dyslipidemia, and albuminuria. Animals were phenotyped for urinary albumin levels at 20 and 28 weeks of age. F1 hybrids exhibit a level of urinary albuminuria intermediate between KK/Ta and BALB/c. 101 polymorphic markers at an average spacing of 12.2 cM and 93% genome coverage were used for the genome scan.
A locus at 83 cM on mouse Chromosome 2 showed significant linkage to urinary albumin levels at 20 and 28 weeks of age with LOD=3.5 near D2Mit311. This locus is named Ua1 (urinary albuminuria 1) and explains 9% of the phenotypic variance. KK/Ta-derived alleles at Ua1 confer increased albuminuria with an incomplete dominant mode of inheritance. Additional analysis revealed interaction between Ua1 and Fbgl1 (fasting blood glucose 1) at 36 cM on mouse Chromosome 12 and Fbgl2 (fasting blood glucose 2) at 10.1 cM on mouse Chromosome 15. Animals homozygous for KK/Ta-derived alleles at Ua1, Fbgl1, and Fbgl2 exhibit the highest urinary albumin levels compared to all other genotypes. The finding suggests that Ua1 increases urinary albumin in individuals with genetic susceptibility for fasting hyperglycemia.
Candidate genes mapping near Ua1 are Hnf4a (94 cM), Ghrh (89 cM), Sstr4 (84 cM), Angpt4 (84 cM), and Thbd (84 cM). A human study mapped type 2 diabetes susceptibility to an interval on human Chromosome 20q13.1-q13.2. This interval has overlapping orthology to the Ua1 interval but authors in the human study determined that HNF4A is not a candidate gene in their familial cases.
Analysis Tools