Dissection of the Renal Failure‐3 QTL

Abstract

Rf‐3, a quantitative trait locus (QTL) on the rat chromosome 3, affects renal disease susceptibility in the FHH (Fawn Hooded Hypertensive) rat. Synergistic interaction between Rf‐3 and other loci such as Rf‐1 had shown to be important in the disease development. Therefore, we used a triple congenic strain, in which Rf‐1, Rf‐3, and Rf‐4 were introgressed onto the genetic background of the renal disease resistant strain ACI (August Copenhagen Irish), to elucidate the genetic control of Rf‐3. The aim of this study was to reduce the Rf‐3 congenic region and identify the disease‐causing gene(s). By developing set of congenic strains we reduced the Rf‐3 region from 110 Mbp to 3.2 Mbp. The congenic strain carrying the reduced Rf‐3 region showed 2 and 3.5‐fold increase in proteinuria and albuminuria, respectively, compared to the control group. Kidney histology also revealed significantly increased protein casting and glomerular sclerosis in the minimal congenic strain. Sequence analysis of the congenic region revealed 2995 sequence variants between the FHH and ACI. We prioritized the variants based on sequence conservation across species and their location. Our analysis found 42 variants in 13 different genes. Two of them, Defb28 and Bcl2l1, are present in the syntenic mouse and human renal function QTL, which makes them potential candidates for future study. Research support: NHLBI‐5R01HL069321 to H.J.J.