Contribution of independent and pleiotropic genetic effects in the metabolic syndrome in a hypertensive rat

Abstract

Hypertension is a major risk factor for cardiovascular disease, Type 2 diabetes, and end organ failure, and is often found concomitant with disorders characteristic of the Metabolic Syndrome (MetS), including obesity, dyslipidemia, and insulin resistance. While the associated features often occur together, the pathway(s) or mechanism(s) linking hypertension in MetS are not well understood. Previous work determined that genetic variation on rat chromosome 17 (RNO17) contributes to several MetS-defining traits (including hypertension, obesity, and dyslipidemia) in the Lyon Hypertensive (LH) rat, a genetically determined MetS model. We hypothesized that at least some of the traits on RNO17 are controlled by a single gene with pleiotropic effects. To address this hypothesis, consomic and congenic strains were developed, whereby a defined fragment of RNO17 from the LH rat was substituted with the control Lyon Normotensive (LN) rat, and MetS phenotypes were measured in the resultant progeny. Compared to LH rats, LH-17LN consomic rats have significantly reduced body weight, blood pressure, and lipid profiles. A congenic strain (LH-17LNc), with a substituted fragment at the distal end of RNO17 (17q12.3; 74–97 Mb; rn4 assembly), showed differences from the LH rat in blood pressure and serum total cholesterol and triglycerides. Interestingly, there was no difference in body weight between the LH-17LNc and the parental LH rat. These data indicate that blood pressure and serum lipids are regulated by a gene(s) in the distal congenic interval, and could be due to pleiotropy. The data also indicate that body weight is not determined by the same gene(s) at this locus. Interestingly, only two small haplotypes spanning a total of approximately 0.5 Mb differ between the LH and LN genomes in the congenic interval. Genes in these haplotypes are strong candidate genes for causing dyslipidemia in the LH rat. Overall, MetS, even in a simplified genetic model such as the LH-17LN rat, is likely due to both independent and pleiotropic gene effects.

Cervical vagal nerve stimulation impairs glucose tolerance and suppresses insulin release in conscious rats

“…) were used including congenic Lyon hypertensive rats with substituted fragments of chromosome 17 (Ma et al. ). These rat strains differ in cardiovascular and metabolic parameters (Vincent et al.…”

“…Some of the rats were previously used as breeders whose offspring were used for another study (Ma et al. ). The characteristics of the individual animals included in this study are presented in Tables and .…”

“…A mixed population of aged (9.7 AE 0.7 months) male and female rats from various Lyon strains (Dupont et al 1973) were used including congenic Lyon hypertensive rats with substituted fragments of chromosome 17 (Ma et al 2017). These rat strains differ in cardiovascular and metabolic parameters (Vincent et al 1993;Wang et al 2015).…”

“…These rat strains differ in cardiovascular and metabolic parameters (Vincent et al 1993;Wang et al 2015). Some of the rats were previously used as breeders whose offspring were used for another study (Ma et al 2017). The characteristics of the individual animals included in this study are presented in Tables 1 and 2.…”

Rat Models of Metabolic Syndrome

“…Overall, the LH strain is a comprehensive MetS model for both physiological and genetic studies. Comprehensive genetic studies in the LH rat determined that MetS is polygenic, with both independent and pleiotropic genetic effects on MetS traits, and combined fine-mapping and systems genetic studies have identified multiple loci and candidate genes [24,22,[25][26][27][28].…”