A major X-linked locus affects kidney function in mice

Abstract

Chronic kidney disease is a common disease with increasing prevalence in the western population. One common reason for chronic kidney failure is diabetic nephropathy. Diabetic nephropathy and hyperglycemia are characteristics of the mouse inbred strain KK/HlJ, which is predominantly used as a model for metabolic syndrome due to its inherited glucose intolerance and insulin resistance. We used KK/HlJ, an albuminuria-sensitive strain, and C57BL/6J, an albuminuria-resistant strain, to perform a quantitative trait locus (QTL) cross to identify the genetic basis for chronic kidney failure. Albumin-creatinine ratio (ACR) was measured in 130 F2 male offspring. One significant QTL was identified on chromosome (Chr) X and four suggestive QTL were found on Chrs 6, 7, 12, and 13. Narrowing of the QTL region was focused on the X-linked QTL and performed by incorporating genotype and expression analyses for genes located in the region. From the 485 genes identified in the X-linked QTL region, a few candidate genes were identified using a combination of bioinformatic evidence based on genomic comparison of the parental strains and known function in urine homeostasis. Finally, this study demonstrates the significance of the X chromosome in the genetic determination of albuminuria.

Fig. 1

Genome scan for log(ACR+1) in 130 F2 male progeny from an intercross between the strains KK and B6. Analysis was performed in males only. The thresholds of significance were calculated based on 1,000 permutation tests for the autosomes and 16,404 permutation tests for Chr X. The dashed line represents the threshold for significant QTLs (P = 0.05, LOD = 3.82 for the autosomes, LOD = 2.74 for Chr X.) The dotted line represents the threshold for suggestive QTLs (P = 0.63, LOD = 2.33 for the autosomes, LOD = 1.54 for Chr X)

Fig. 2

Chromosome scans and allele effect plots for main effect QTLs. The chromosome-specific scan of each main effect QTL is depicted followed by the effect plot at the peak location. The thresholds for significant and suggestive QTL are represented by the dashed and dotted lines, respectively, as described in Fig. 1. In the allele effect plots, KK indicates mice homozygous for the KK allele, BK indicates mice heterozygous with both a KK and B6 allele, and BB indicates mice homozygous for the B6 allele. ACR is depicted as the mean of log10(ACR+1) ± SE per genotype at each locus