Quantitative trait loci for urinary albumin in crosses between C57BL/6J and A/J inbred mice in the presence and absence of Apoe

Abstract

We investigated the effect of apolipoprotein E (Apoe) on albuminuria in the males of two independent F2 intercrosses between C57BL/6J and A/J mice, using wild-type inbred strains in the first cross and B6-Apoe(-/-) animals in the second cross. In the first cross, we identified three quantitative trait loci (QTL): chromosome (Chr) 2 [LOD 3.5, peak at 70 cM, confidence interval (C.I.) 28-88 cM]; Chr 9 (LOD 2.0, peak 5 cM, C.I. 5-25 cM); and Chr 19 (LOD 1.9, peak 49 cM, C.I. 23-54 cM). The Chr 2 and Chr 19 QTL were concordant with previously found QTL for renal damage in rat and human. The Chr 9 QTL was concordant with a locus found in rat. The second cross, testing only Apoe(-/-) progeny, did not identify any of these loci, but detected two other loci on Chr 4 (LOD 3.2, peak 54 cM, C.I. 29-73 cM) and Chr 6 (LOD 2.6, peak 33 cM, C.I. 11-61 cM), one of which was concordant with a QTL found in rat. The dependence of QTL detection on the presence of Apoe and the concordance of these QTL with rat and human kidney disease QTL suggest that Apoe plays a role in renal damage.

Figure 1.—

Distribution of the albumin/creatinine ratio (ACR) in cross 1 (A) and cross 2 (B).

Figure 2.—

Genomewide scans for albuminuria using nonparametric analysis for (A) cross 1 and (B) cross 2. The dotted line at the top depicts a significant LOD score (P < 0.05) and the dotted line at the bottom a suggestive LOD score (P < 0.63).

Figure 3.—

Allele effects for the loci found in cross 1. Homozygosity for A/J alleles is represented by AA, homozygosity for C57BL/6J alleles by BB, and heterozygosity by AB. The SNP at which the allele effect is determined is shown under each graph.

Figure 4.—

Allele effects for the loci found in cross 2. Homozygosity for A/J alleles is represented by AA, homozygosity for C57BL/6J alleles by BB, and heterozygosity by AB. The SNP at which the allele effect is determined is shown under each graph.

Figure 5.—

Using comparative genomics and interval-specific haplotype analysis to narrow the chromosome 2 QTL. Comparing the C.I. of our cross with the interval on rat Chr 3 found in the (FHH × ACI) F₂ intercross and the human chromosome 20 interval narrowed the region to 51 Mb. Interval-specific haplotype analysis of this region, comparing SNPs between B6 and A, resulted in three regions that have different haplotypes between the strains and contain 343 genes according to the Ensembl database (release 42).