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

Authors: Herrera, VL  Ponce, LR  Ruiz-Opazo, N 
Citation: Herrera VL, etal., J Hypertens. 2007 Aug;25(8):1608-12.
Pubmed: (View Article at PubMed) PMID:17620956
DOI: Full-text: DOI:10.1097/HJH.0b013e328182df1a

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.


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CRRD Object Information
CRRD ID: 2290428
Created: 2008-03-12
Species: All species
Last Modified: 2008-03-12
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.