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.
Highlights
Hypertension is a major risk factor for morbidity and mortality from heart disease, stroke, and renal failure
The consomic strain has all of RNO17 derived from the Lyon Normotensive (LN) rat, while the rest of the genome, including the sex chromosomes and mitochondrial DNA, are from the Lyon Hypertensive (LH) rat
The primary hypothesis for these studies is that the Metabolic Syndrome (MetS) traits mapping to LH chromosome 17 are caused by a gene(s) with pleiotropic effects or by passenger loci fixed in the selection for hypertension in the LH strain
Summary
Hypertension is a major risk factor for morbidity and mortality from heart disease, stroke, and renal failure. Blood pressure (BP) is a complex trait, controlled by a series of networks, involving multiple organ systems, and is affected by genes and environment stimuli. While genetic susceptibility is established in hypertension [3], and significant insight has been established by studying rare monogenic forms of hypertension [4], the heterogeneity of mechanisms leading to hypertension presents a challenge for identifying variants with major effects and creates a key gap in knowledge for fully understanding and effectively treating the disease. Some of the underlying genetic factors for MetS-associated hypertension may be due to pleiotropy (single gene/variant causes multiple phenotypes). To date the number of genes identified with pleiotropy involving blood pressure is limited, possibly due to the relatively low effect sizes of the variants identified in hypertension GWAS as well as high heterogeneity between populations
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