Mapping of genetic loci predisposing to hypertriglyceridaemia in the hereditary hypertriglyceridaemic rat: analysis of genetic association with related traits of the insulin resistance syndrome

Abstract

Aims/hypothesis. Hypertriglyceridaemia is an important risk factor for coronary heart disease, especially in the context of the insulin resistance syndrome where it often occurs with hypertension. The two phenotypes are also associated in the hereditary hypertriglyceridaemic (hHTg) rat. The aim of this study was to map quantitative trait loci that affect plasma triglyceride concentration in the hHTg rat and determine whether they co-localize with loci for blood pressure. Methods. Second filial generation progeny (n=189) from a cross of the hHTg rat with the Brown Norway rat were phenotyped for fasting plasma triglyceride, glucose and insulin concentrations, and direct unrestrained resting blood pressure. A partial genome-scan was conducted using 153 microsatellite markers that were polymorphic between the two strains. Results. A major locus (lod score 6.5) influencing plasma triglyceride concentration in a co-dominant fashion was mapped to chromosome 4 between D1Mit5 and D1Mit17. Chromosome 8 contained multiple peaks with a lod score greater than 4.0 influencing triglyceride concentration. Importantly, none of the triglyceride loci had an effect on blood pressure. The triglyceride locus on chromosome 4 co-localized with a locus for fasting plasma insulin (lod score 4.1), although the effect on insulin concentration was in the opposite direction to that on triglyceride. Conclusion/interpretation. We have mapped the major loci that affect plasma triglyceride concentration in the hHTg rat. These loci do not influence blood pressure suggesting that these commonly associated phenotypes of the insulin resistance syndrome are not be due to pleiotropic effects of the same gene(s). [Diabetologia (2003) 46:352-358]

Genetic control of plasma lipid levels in a cross derived from normoglycaemic Brown Norway and spontaneously diabetic Goto–Kakizaki rats

“…In rats the genetic control of plasma lipid variables has been addressed in the context of hypertension [23][24][25], stroke [25], obesity [26] and hypertriglyceridaemia [27] using experimental crosses and mapping panels derived from genetically different inbred control and disease strains. Here we identify a new locus Pl/gk1 that co-localises with a QTL linked to the level of plasma triglycerides and cholesterol in a cross derived from the spontaneously obese Otsuka Long-Evans Tokushima Fatty (OLETF) strain [27]. The QTL Tchol/gk1 also overlaps with loci linked to serum cholesterol levels identified in two crosses between the spontaneously hypertensive rat, stroke-prone (SHRSP) and Wistar Kyoto strains [25], and between Dahl hypertensive (SS) and Dahl normotensive (SR) rats [24].…”

Protein remodeling of the heart ventricles in hereditary hypertriglyceridemic rat: effect of ace-inhibition

“…Nonobese, hereditary hypertriglyceridemic (hHTG) rats provide an interesting model of hypertension associated with hypertriglyceridaemia and glucose intolerance [4,5]. This model of LVH is also characterized by adrenergic overactivity and insulin resistance [6], and mimics the well known metabolic syndrome in man.…”

“…This model of LVH is also characterized by adrenergic overactivity and insulin resistance [6], and mimics the well known metabolic syndrome in man. Despite numerous studies performed on this model investigating humoral [6,7], metabolic [8][9][10], and genotype alterations [5], there is little data focused on cardiovascular system disorders [11][12][13]. Pressure haemodynamic overload can be expected to induce the adaptive growth of the heart, and alteration of vascular and myocardial structure, which could be modified by the specific neurohormonal and metabolic disorders.…”

Dynamic genetic architecture of metabolic syndrome attributes in the rat

“…Whereas the region between markers D8Rat36 and D8Rat75 showed linkage to several morphometric traits, the second one (D8Rat43-D8Got72) showed significant linkage to TG concentrations in dexamethasone-treated rats. The latter region has been linked to the various aspects of metabolic and hemodynamic derangements in humans and model organisms (18,22,41). The confidence interval for the TG QTL lies within the differential segment of PD/Cub origin in the previously established BN.PD-D8Rat39/D8Rat35 (BN-Lx/Cub, Rat Genome Database ID no.…”