Genetics
Three newly discovered rat gene loci determine whether human CETP causes severe hypercholesterolemia when expressed as a transgene (J Hypertens 2007)
Original title: Genome-wide scan for interacting loci affecting human cholesteryl ester transfer protein-induced hypercholesterolemia in transgenic human cholesteryl ester transfer protein F2-intercross rats
Building on the finding that transgenic expression of human CETP (hCETP) causes severe combined hyperlipidemia and coronary atherosclerosis susceptibility in Dahl S rats but not in other genetic backgrounds (Dahl R, spontaneously hypertensive rats), this study performed a genome-wide scan for quantitative trait loci (QTL) that modify hCETP-mediated hypercholesterolemia, genotyping 159 male F2 intercross rats transgenic for the hCETP transgene with 121 polymorphic markers. Three novel hCETP-dependent QTL for hypercholesterolemia were identified: one on chromosome 3 with suggestive linkage (LOD 2.26), one on chromosome 9 with significant linkage (LOD 4.15), and one on chromosome 11 with significant linkage (LOD 3.48), none previously detected in other rat intercrosses. The authors conclude these CETP-interacting loci could partly explain the controversy over the atherogenic role of CETP in humans, suggesting interacting genes may confound or modulate CETP-mediated pro-atherogenic susceptibility.
Original abstract
Objective: We documented susceptibility in Dahl S rats to coronary atherosclerosis upon the transgenic expression of human cholesteryl ester transfer protein (hCETP) producing severe combined hyperlipidemia, as detected in Tg[hCETP]53 (Tg53) Dahl S rats. In other genetic backgrounds (i.e. Dahl R, spontaneously hypertensive rat strains) transgene expression does not lead to severe combined hyperlipidemia. This study aimed to identify genetic loci that modify the effect of hCETP on hypercholesterolemia observed in different genetic contexts.
Methods: To identify quantitative trait loci (QTL) that affect hCETP-mediated hyperlipidemia in Tg53 Dahl S rats in contrast to Tg53 Dahl R rats we performed a genome-wide scan for QTL affecting plasma total cholesterol in an F2[Tg (R x S)]-intercross male population (n = 159) that are transgenic for the Tg[hCETP]53 transgene. Hybrids were genotyped with 121 informative polymorphic markers.
Results: We detected three novel hCETP-dependent QTL for hypercholesterolemia: one on chromosome 3 with suggestive linkage [logarithm of odds score derived from likelihood ratio statistic using a factor of 4.6 (LOD) 2.26]; one on chromosome 9 with significant linkage (LOD 4.15), and one on chromosome 11 with significant linkage (LOD 3.48) that have not been detected in other rat intercrosses.
Conclusion: Three cholesteryl ester transfer protein (CETP)-interacting loci were identified in a Tg53 Dahl S rat intercross study affecting cholesterol metabolism. These results could partly explain the controversy regarding the atherogenic role of CETP in humans, suggesting the hypothesis that putative CETP interacting genes confound or play an important role in CETP-mediated pro-atherogenic susceptibility in humans. Overall, these observations reiterate the key role of epistasis in complex, multifactorial traits.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.