Epistatic effects of multiple congenic regions on blood pressure and heart weight in Dahl rats under salt‐loading conditions

Mammalian complex traits are little studied for combinatorial gene‐gene interactions. To study epistasis among blood pressure (BP) quantitative trait loci (QTLs) we developed bi‐and tri‐congenic strains that introgress R‐rat congenic regions containing RNO3, RNO7, and RNO9 low BP alleles into S rats. S rats, RNO3+RNO7+RNO9 tri‐congenic, and RNO3+RNO7, RNO3+RNO9, and RNO7+RNO9 bi–congenic rats (n=16) were concomitantly raised on a low (0.4% NaCl) salt diet until 6 weeks‐old, fed a higher (2% NaCl) salt diet for 24 days, after which tail‐cuff BP, body weight (BW), and heart weight (HW) were measured. While all bi‐ and tri‐congenic strains had lower BP (P<0.0001) compared to the parental, S, strain, BP differences were not observed among the bi‐ and tri‐congenic strains. Thus, low BP alleles in the congenic regions were non‐additive under this salt‐loading condition. While bi‐ and tri‐congenic strains had significantly lower HW (P<0.0001) compared to S rats, only RNO3+RNO7+RNO9 and RNO3+RNO7 rats had lower BW‐adjusted HW (1201.8 and 1128.0 mg, respectively) compared to S rats (1267.2 mg; P=0.004 and P<0.0001, respectively). Thus, low BP QTL‐containing alleles showed non‐additive effects, while RNO3+RNO7 bicongenic rats having lower BW‐adjusted HW compared with RNO3+RNO7+RNO9 rats (P<0.002). These results provide evidence for strong interactions between previously identified BP QTLs.