Journal Article

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

Toshihide Shike, Tomohito Gohda, Mitsuo Tanimoto, Michimasa Kobayashi, Yuichiro Makita, Kazuhiko Funabiki, Satoshi Horikoshi, Sachiko Hirose, Toshikazu Shirai and Yasuhiko Tomino

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 20, issue 5, pages 879-885
Published in print May 2005 | ISSN: 0931-0509
Published online March 2005 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfh665
Chromosomal mapping of a quantitative trait locus for the development of albuminuria in diabetic KK/Ta mice

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Background. 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.

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

Results. 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 (χ2 = 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.

Conclusions. 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.

Keywords: Diabetic Nephropathy; KK/Tamice; albuminuria; QTL

Journal Article.  3725 words.  Illustrated.

Subjects: Nephrology

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