Genome-wide scan for interacting loci affecting human cholesteryl ester transfer protein-induced hypercholesterolemia in transgenic human cholesteryl ester transfer protein F2-intercross rats

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 TghCETP]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 F2Tg (R x S)]-intercross male population (n = 159) that are transgenic for the TghCETP]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.