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Human Molecular Genetics Advance Access originally published online on September 30, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 23 3097-3107
DOI: 10.1093/hmg/ddg333
© 2003 Oxford University Press

Multiple quantitative trait loci modify the heart failure phenotype in murine cardiomyopathy

Philippe Le Corvoisier1,2, Hyun-Young Park1,2, Kerri M. Carlson2, Douglas A. Marchuk2 and Howard A. Rockman1,2,*

1Department of Medicine and 2Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, 27710, USA

Received July 29, 2003; Revised September 17, 2003; Accepted September 23, 2003

The variability in outcome of heart failure patients depends on a number of factors including differences in their genetic background. To identify novel genes that modify the human heart failure phenotype, we used a strategy of quantitative trait locus (QTL) mapping in an experimental mouse model of dilated cardiomyopathy induced by cardiac-specific overexpression of calsequestrin and characterized by a strong strain-specific variability in the phenotype. We identified two novel QTLs, Hrtfm3 (heart failure modifier 3) on chromosome (Chr) 4 and Hrtfm4 on Chr 18, significantly linked to survival with likelihood ratio statistics (LRS) of 19.9 and 23.6 respectively (corresponding to LOD scores of 4.3 and 5.1). Two other QTLs, Hrtfm5 on Chr 2 and Hrtfm6 on Chr 13, were significantly linked to cardiac function as measured by echocardiographic fractional shortening (LRS 22.1 and 15.2 respectively, LOD score 4.8 and 3.3) and left ventricular end-diastolic diameter (LRS 23.5 and 18.8, LOD score 5.1 and 4.1). Importantly, Hrtfm5 was not significantly linked to survival. A significant interaction was found between Hrtfm4 and two other QTLs (Hrtfm6 and a QTL near to the marker D19Mit88) for fractional shortening with a LRS of 34.6 and 26.5 respectively (LOD score 7.5 and 5.8). These data show that the effect of genetic background on murine heart failure is complex and result from the action of several loci that differentially modify the cardiac phenotype. The identification of these novel modifier genes will serve as strong candidates for the discovery of modifiers in human heart failure.

* To whom correspondence should be addressed at: Department of Medicine, Molecular Genetics and Microbiology, Duke University Medical Center, CARL Building Room 226, DUMC 3104, Durham, NC 27710, USA. Tel: +1 9196682520; Fax: +1 9196682524; Email: h.rockman{at}duke.edu


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