Abstract P638: Investigating Gene Pleiotropy in the Metabolic Syndrome in Lyon Hypertensive Rats

Abstract

The metabolic syndrome (MetS) - hypertension, obesity, dyslipidemia, and insulin resistance - is a major risk factor for cardiovascular disease and stroke. Our overall goal is to identify novel genes and pathways causing MetS. Our previous work determined that rat chromosome 17 (RNO17) contributes to several MetS-defining traits (including high blood pressure, obesity, and dyslipidemia) in the Lyon Hypertensive (LH) rat, a genetically determined MetS rat 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, we generated congenic strains where a defined fragment of RNO17 from the LH rat was substituted by that of the control Lyon Normotensive (LN) rat, and measured MetS phenotypes. One congenic (LH-17 LN a), with the proximal 30 Mb of RNO17 from the LH genome substituted with that of the LN genome, did not show significant differences from the LH parental strain. However, another congenic strain (LH-17 LN c), with a substituted fragment at the distal end of RNO17 (84-97 Mb), showed significant differences from the LH rat in serum total cholesterol (3.15 ± 0.15 vs. 4.29 ± 0.17 mMol; p<0.01) and triglycerides (0.47 ± 0.06 vs. 1.27± 0.13 mMol; p<0.001), and a trend for reduced blood pressure (SBP 150.8 ± 3.4 vs. 157.1 ± 1.7 mmHg; p=0.1). Interestingly, there was no difference in body weight between the LH-17 LN c and the parental LH rat (440 + 7.2 vs. 435 + 9.1 g). These data indicate that serum cholesterol and triglycerides, and possibly blood pressure are regulated by a gene(s) in the distal congenic interval, and could be due to pleiotropy. The data also indicate body weight is not determined by the same gene(s). Interestingly, only two small haplotypes spanning a total of 1 Mb differ between the LH and LN genomes in the congenic interval. Genes in these haplotypes are being studied as candidate genes for causing dyslipidemia in the LH rat. Overall MetS, even in a simplified genetic model such as the LH-17 LN rat, is likely due to both independent and pleiotropic gene effects.