Integrating human and rodent data to identify the genetic factors involved in chronic kidney disease

Abstract

The increasing numbers of patients with chronic kidney disease combined with no satisfying interventions for preventing or curing the disease emphasize the need to better understand the genes involved in the initiation and progression of complex renal diseases, their interactions with other host genes, and the environment. Linkage and association studies in human, rat, and mouse have been successful in identifying genetic loci for various disease-related phenotypes but have thus far not been very successful identifying underlying genes. The purpose of this review is to summarize the progress in human, rat, and mouse genetic studies to show the concordance between the loci among the different species. The collective utilization of human and nonhuman mammalian datasets and resources can lead to a more rapid narrowing of disease loci and the subsequent identification of candidate genes. In addition, genes identified through these methods can be further characterized and investigated for interactions using animal models, which is not possible in humans.

Figure 1.

Ideograms of human chromosomes with concordant human, mouse, and rat CKD loci are shown. Human CKD loci identified using linkage (blue) and GWA studies (O-) are indicated on the left side of the chromosome. Concordant loci found in rat (green) and mouse (purple) are shown on the right side of the chromosome.

Figure 2.

Comparative map shows overlap of renal susceptibility loci between rat and human. The physical map of the rat QTL on chromosome 2 is shown on the left. The proteinuria QTL was successfully narrowed to a small genomic segment through congenic strain analysis. The region in human that is homologous to the rat QTL lies on both human chromosomes 1 and 4. No linkage for any renal-related traits has been observed on human chromosome 4 (151 to 155 Mb), whereas linkage with human chromosome 1 (152 to 157 Mb) has been observed in several studies.^,, Taken together, the region of concordance between the rat and human (1q21) allows the rat QTL to be narrowed by approximately 50%, along with the number of likely candidate genes. Map distances are in base pairs (www.ensembl.org, Ensembl v38; April 2006). Reproduced with permission from APS.

Figure 3.

Comparative mapping identifies FRMD3 as a novel CKD locus in human and mouse. (A) The 2-Mb interval on chromosome 9 flanking associations identified in the GWA study of the GoKinD collection contains 10 annotated genes. The proximal 1-Mb region is homologous with a region on mouse chromosome 4 that is linked to albuminuria QTL that have been mapped in two crosses ((C57BL/6J × DBA/2J/)F2 and (C57BL/6J × NZM)F1 × NZM), whereas the distal 1-Mb region is homologous to a region on mouse chromosome 13 for which no linkage with renal phenotypes has been found. On the basis of the overlapping signal, concordance mapping at this locus implicates only RASEF and FRMD3 as potential candidate CKD genes. (B) QTL mapping detects chromosomal regions that contain genetic variance between the strains used in a particular cross. Regions that are genetically identical between the two strains, conversely, cannot be linked to the trait of interest. The black bars indicate the regions that are genetically different between the parental strains used for the two crosses. Because haplotype information was not available for NZM, we used data from NZB and NZW, which are the progenitors of NZM. Because RASEF is in a region with no genetic variance in both the C57BL/6JxDBA/2J and C57BL/6Jx SM crosses, FRMD3 is the most likely candidate gene for this concordant locus in human and mouse.

Figure 4.

Interval-specific haplotyping and human concordance narrow a locus for albuminuria. A QTL for albuminuria was found on the distal part of mouse chromosome 2 in multiple crosses. Interval-specific haplotyping eliminates the regions in which the two parental strains for each cross were genetically identical and resulted in three small intervals with 14, 60, and 13 genes, respectively. The proximal region is homologous to human chromosome 20p, for which linkage was found in human, whereas the distal region is homologous to human chromosome 20q, for which no linkage has been found. On the basis of the concordance at both the mouse and human loci, the candidate gene is most likely among the 14 genes within the proximal region.