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

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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.
RGD ID: 2290428
Pubmed: PMID:17620956   (View Abstract at PubMed)
DOI: DOI:10.1097/HJH.0b013e328182df1a   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Scl54RatHypercholesterolemia  IAGP  RGD 
Scl55RatHypercholesterolemia  IAGP tends to decreaseRGD 
Scl56RatHypercholesterolemia  IAGP  RGD 
Scl57RatHypercholesterolemia  IAGP  RGD 
Scl58RatHypercholesterolemia  IAGP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Scl54Ratincreased cholesterol level  IDA  RGD 
Scl55Ratincreased cholesterol level  IDA  RGD 
Scl56Ratincreased cholesterol level  IDA  RGD 
Scl57Ratincreased cholesterol level  IDA  RGD 
Scl58Ratincreased cholesterol level  IDA  RGD 

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Objects Annotated

QTLs
Scl54  (Serum cholesterol level QTL 54)
Scl55  (Serum cholesterol level QTL 55)
Scl56  (Serum cholesterol level QTL 56)
Scl57  (Serum cholesterol level QTL 57)
Scl58  (Serum cholesterol level QTL 58)

Strains
SR/JrHsd  (Dahl Salt-Resistant)
SS-Tg(ApoC3-CETP)53Opaz  (NA)

Objects referenced in this article
QTL SCL103_H Serum cholesterol level QTL 103 (human) Homo sapiens
QTL SCL37_H Serum cholesterol level QTL 37 (human) Homo sapiens
Strain SS-Tg(ApoC3-CETP)25Opaz null Rattus norvegicus

Additional Information