Isolation and high-throughput sequencing of two closely linked epistatic hypertension susceptibility loci with a panel of bicongenic strains

Abstract

Interactions or epistasis between genetic factors may contribute to "missing heritability." While linkage analyses detect epistasis, defining the limits of the interacting segments poses a significant challenge especially when the interactions are between loci in close proximity. The goal of the present study was to isolate two such epistatic blood pressure (BP) loci on rat chromosome 5. A panel of S.LEW bicongenic strains along with the corresponding monocongenic strains was constructed. BP of each set comprising of one bicongenic and two corresponding monocongenic strains were determined along with the parental Salt-sensitive (S) strain. Epistasis was observed in one out of four sets of congenic strains, wherein systolic blood pressures (SBP) of the two monocongenic strains S.LEW(5)x6Bx9x5a and S.LEW(5)x6Bx9x5b were comparable to that of S, but the SBP of the bicongenic strain S.LEW(5)x6Bx9x5 (157 ± 4.3 mmHg) was significantly lower than that of S (196 ± 6.8 mmHg, P < 0.001). A two-way ANOVA indicated significant interactions between the LEW alleles at the two loci. The interacting loci were 2.02 Mb apart and located within genomic segments spanning 7.77 and 4.18 Mb containing 7,360 and 2,753 candidate variants, respectively. The current study demonstrates definitive evidence for epistasis and provides genetic tools for further dissection of the isolated epistatic BP loci.

Evidence for a link between gut microbiota and hypertension in the Dahl rat

“…Pups were weaned at 4 wk of age and continued to be maintained on a low-salt diet for experiments conducted under lowsalt conditions or fed a high salt (2% NaCl)-containing diet (Harlan Teklad, TD94217) for experiments conducted under high-salt conditions. The animals were implanted with C-10 transmitters (Data Sciences International, St. Paul, MN) as described previously (37) to record systolic BP via radiotelemetry. After the animals recovered from surgery, a baseline systolic BP reading was recorded for 1 h (T ϭ 0 h).…”

Dr Lewis Kitchener Dahl, the Dahl Rats, and the “Inconvenient Truth” About the Genetics of Hypertension

“…gene-gene interactions between mapped loci for blood pressure on the rat genome. Examples include epistasis between loci on two different chromosomes 96, 104 and loci that are closely-linked on the same chromosome 92, 105 . For a modeling of epistasis with case-studies of experimental data obtained using the Dahl rat studies on the genetics of hypertension, readers are referred to a recent theoretical article 106 .…”

Pathway-Guided Identification of Gene-Gene Interactions

“…The focus of genetic association studies for complex diseases has been gradually shifting from assessing the main genetic effect to assessing interaction effects among genes (Cordell, ). Complex diseases, such as hypertension, cancer, diabetes, and psychiatric disorders are believed to have a polygenic basis and gene‐gene interaction (GxG) may play significant roles in disease etiology (Howson et al., ; Koh‐Tan et al., ; Lin et al., ; Pillai et al., ; Ziyab et al., ). Understanding GxG may also help to uncover missing heritability (Marchini et al., ; Evans et al., ) and to explain inconsistent findings from main‐effect analyses (Hirschhorn et al., ).…”