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 F 2 intercrosses between C57BL/6J and A/J mice, using wild-type inbred strains in the first cross and B6-Apoe À/À 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 À/À 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.

APOL1 Variants Increase Risk for FSGS and HIVAN but Not IgA Nephropathy

“…These mice had a minor but statistically significant increase in albuminuria compared with parental strains (22.1 Ϯ 3.7 versus 6.4 Ϯ 2.8, P ϭ 0.02; Figure 2), but this level of albuminuria was well within the range of normal variation for inbred strains (reported range 3 to 142 g albumin/mg creatinine). 19,24,25 We confirmed that Myh9 expression was significantly decreased (by 30%) in Myh9 ϩ/Ϫ mice compared with wild-type littermates (Supplemental Figure 1), which was comparable to the reduction observed in the TgFVB strain. 22 This suggests that reduced Myh9 expression in the TgFVB strain occurs secondary to glomerulosclerosis and is likely not causal in the development of nephropathy.…”

Influence of genetic background on ex vivo and in vivo cardiac function in several commonly used inbred mouse strains

“…Future studies could center on tracking and identification of QTL that modify particular cardiac disease-related physiological processes. Previous studies have demonstrated the feasibility of using the genetic homogeneity of inbred mouse strains to isolate and identify physiologically significant QTL (2,6,13,20,21,48,49). In this study, we observed significant functional differences between inbred strains that were evident when subjected to the stresses of ischemia/reperfusion, ␤-blockade, and acute hypoxia.…”

“…Even in the absence of engineered or known naturally occurring mutations, different inbred mouse strains can vary drastically in their susceptibility to clinically relevant diseases. Previous reports have taken advantage of this naturally occurring variation in susceptibility to a particular disease to identify quantitative trait loci (QTL) that modify disease pathogenesis (2,6,13,48,49).…”

FVB mouse genotype confers susceptibility to OVE26 diabetic albuminuria

“…A portion of the peak on chromosome 13 is orthologous to human region 7p13-15, which contains a locus previously associated with albuminuria (14). The chromosome 19 peak has a 95% CI from 0 to 36 cM, which overlaps the chromosome 19 QTL peak at 24 cM, previously linked with mouse albuminuria (5). The 95% CI of our mouse chromosome 19 peak corresponds to human genomic regions 9q21-q24, 10q11-q26, and 11q12-q13.…”