Genetic analysis of albuminuria in a cross between C57BL/6J and DBA/2J mice

Chronic kidney disease (CKD) is a growing medical problem and a significant risk factor for the development of end-stage renal disease, cardiovascular disease, and cardiovascular mortality. The genetic basis of CKD is recognized, but knowledge of the specific genes that contribute to the onset and progression of kidney disease is limited, mainly because of the difficulty and expense of identifying genes underlying CKD in humans. Results from genetic studies of CKD in rodents often correspond to findings in humans; therefore, we used quantitative trait locus (QTL) analysis to detect genomic regions affecting albuminuria in a cross between C57BL/6J and DBA/2J mice, strains resistant and susceptible to CKD, respectively. We identified several independent and interacting loci affecting albuminuria, including one QTL on mouse chromosome (Chr) 2 that is concordant with QTL influencing urinary albumin excretion on rat Chr 3 and diabetic nephropathy on human Chr 20p. Because this QTL was identified in multiple mouse crosses, as well as in rats and in humans, we used comparative genomics, haplotype analysis, and expression profiling to narrow the initial QTL interval from 386 genes to 10 genes with known coding sequence polymorphisms or expression differences between the strains. These results support the continued use of multiple cross-mapping and cross-species comparisons to further our understanding of the genetic basis of kidney disease.