Abstract P117: Blood Pressure Heterosis And Genotype-Specific Regulation Of C17h6orf52

Abstract

Although blood pressure (BP) is highly heritable, the genetic etiology is complex, and causative genes do not completely explain observed variation. Using the Lyon Hypertensive (LH) rat—a well-characterized polygenic inbred model—we previously identified a novel candidate gene ( C17h6orf52 ) as a master regulator of gene expression regulating cardiometabolic traits. CRISPR-Cas9 gene editing was used to generate a mutation in C17h6orf52 , and blood pressure in homozygous wildtype (WT), heterozygous (HET) and homozygous mutant (MUT) females was characterized via radiotelemetry. Herein, we show evidence of BP heterosis (i.e. hybrid vigor) in females from the C17h6orf52 strain. Systolic (SBP) and diastolic (DBP) pressures (mmHg) were determined in WT, HET, and MUT male and female rats on normal chow (CHOW), and 4% salt (NaCl) diet (to determine salt sensitivity). All measures are presented as mean±SEM, and significant results are indicated according to statistical test. No significant differences were identified in males, but the HET females (n=5) had significantly lower systolic blood pressure than either WT (n=7) or MUT (n=8) at both baseline and salt-stressed conditions: SBP-CHOW: (WT: 144±3.28; HET: 136.0±0.83 * ; MUT: 142.6±2.13)DBP-CHOW: (WT: 98.3±2.29; HET: 94.0±0.68; MUT: 97.4±1.76)SBP-NaCl: (WT: 150.4±3.40; HET: 142.2±1.19 * ; MUT: 150.2±1.83)DBP-NaCl: (WT: 103.3±2.75; HET: 98.2±1.68; MUT: 103.1±1.68) Tissues were collected to assess C17h6orf52 expression relative to WT, displayed below as confidence intervals. While there were no differences between WT and MUT expression, liver C17h6orf52 was significantly overexpressed in heterozygous females. C17h6orf52 2^-ddCT: (WT: 0.91-1.09, n=8; HET: 1.33-1.73 $ , n=5; MUT: 0.85-1.19, n=8) There were no striking differences in any metabolic phenotypes, such as body weight and adiposity, thus these data suggest that C17h6orf52 is protective against increases in blood pressure specifically. Continued study will attempt to tease apart allele-specific regulation and protein functions in heterozygous animals of both sexes. * p<0.05 by Kruskal-Wallis $ p<0.05 by 1-WAY ANOVA