Le Corvoisier Philippe, Park Hyun-Young, Carlson Kerri M, Marchuk Douglas A, Rockman Howard A
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Hum Mol Genet. 2003 Dec 1;12(23):3097-107. doi: 10.1093/hmg/ddg333. Epub 2003 Sep 30.
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.
心力衰竭患者预后的变异性取决于多种因素，包括他们基因背景的差异。为了识别改变人类心力衰竭表型的新基因，我们在一个由肌浆网钙结合蛋白心脏特异性过表达诱导的扩张型心肌病实验小鼠模型中，采用了数量性状基因座（QTL）定位策略，该模型的特点是表型存在强烈的品系特异性变异性。我们识别出两个新的QTL，位于4号染色体（Chr）上的Hrtfm3（心力衰竭修饰因子3）和位于18号染色体上的Hrtfm4，它们与生存率显著相关，似然比统计量（LRS）分别为19.9和23.6（对应LOD值为4.3和5.1）。另外两个QTL，位于2号染色体上的Hrtfm5和位于13号染色体上的Hrtfm6，与通过超声心动图缩短分数测量的心脏功能显著相关（LRS分别为22.1和15.2，LOD值为4.8和3.3）以及左心室舒张末期直径（LRS为23.5和18.8，LOD值为5.1和4.1）。重要的是，Hrtfm5与生存率无显著关联。发现Hrtfm4与另外两个QTL（Hrtfm6和靠近标记D19Mit88的一个QTL）之间存在显著的相互作用，对于缩短分数，LRS分别为34.6和26.5（LOD值为7.5和5.8）。这些数据表明基因背景对小鼠心力衰竭的影响是复杂的，是由几个不同修饰心脏表型的基因座的作用导致的。这些新的修饰基因的识别将成为发现人类心力衰竭修饰因子的有力候选者。
