Background

Hypertrophic cardiomyopathy (HCM) severity greatly varies among patients even with the same HCM gene mutations. This variation is largely regulated by modifier gene(s), which, however, remain largely unknown. The current study is aimed to identify modifier genes using BXD strains, a large murine genetic reference population (GRP) derived from crosses between C57BL/6 J (B6) and D2 DBA/2 J (D2) mice. D2 mice is a natural model that carry the genetic basis and phenotypes of HCM.

Methods

Myocardial hypertrophy, the major phenotype of HCM, was determined by cardiomyocyte size on cardiac sections in 30 BXD strains, and their parental B6 and D2 strains and morphometric analysis was performed. Quantitative Trait Locus (QTL) mapping for cardiomyocyte sizes was conducted with WebQTL in GeneNetwork. Correlation of cardiomyocyte size and cardiac gene expression in BXDs accessed from GeneNetwork were evaluated. QTL candidate genes associated with cardiomyocyte sizes were prioritized based on the score system.

Results

Cardiomyocyte size varied significantly among BXD strains. Interval mapping on cardiomyocyte size data showed a significant QTL on chromosome (Chr) 2 at 66– 73.5 Mb and a suggestive QTL on Chr 5 at 20.9–39.7 Mb. Further score system revealed a high QTL score for Xirp2 in Chr 2. Xirp2 encodes xin actin-binding repeat containing 2, which is highly expressed in cardiac tissue and associate with cardiomyopathy and heart failure. In Chr5 QTL, Nos3, encoding nitric oxide synthase 3, received the highest score, which is significantly correlated with cardiomyocyte size.

Conclusion

These results indicate that Xirp2 and Nos3 serve as novel candidate modifier genes for myocardial hypertrophy in HCM. These candidate genes will be validated in our future studies.

中文翻译：

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鉴定肥厚性心肌病的修饰基因。

背景

即使具有相同的 HCM 基因突变，肥厚型心肌病 (HCM) 的严重程度也会因患者而异。这种变异在很大程度上受修饰基因的调节，然而，修饰基因在很大程度上仍然未知。目前的研究旨在使用 BXD 菌株鉴定修饰基因，BXD 菌株是一种大型鼠类遗传参考种群 (GRP)，来源于 C57BL/6 J (B6) 和 D2 DBA/2 J (D2) 小鼠之间的杂交。D2 小鼠是携带 HCM 遗传基础和表型的天然模型。

方法

心肌肥大是 HCM 的主要表型，通过 30 个 BXD 菌株的心脏切片上的心肌细胞大小来确定，并对其亲本 B6 和 D2 菌株进行形态分析。使用 GeneNetwork 中的 WebQTL 对心肌细胞大小进行数量性状基因座( QTL) 定位。评估了从 GeneNetwork 访问的 BXD 中心肌细胞大小和心脏基因表达的相关性。根据评分系统对与心肌细胞大小相关的 QTL 候选基因进行优先排序。

结果

BXD 菌株之间的心肌细胞大小差异很大。心肌细胞大小数据的区间作图显示 2 号染色体 (Chr) 上的显着 QTL 为 66-73.5 Mb，Chr 5 上的提示性 QTL 为 20.9-39.7 Mb。进一步的评分系统揭示了 Xirp2 在 Chr 2 中的高 QTL 评分。Xirp2 编码包含 2 的 xin 肌动蛋白结合重复序列，其在心脏组织中高表达并与心肌病和心力衰竭相关。在 Chr5 QTL 中，编码一氧化氮合酶 3 的 Nos3 得分最高，与心肌细胞大小显着相关。

结论

这些结果表明 Xirp2 和 Nos3 可作为 HCM 心肌肥大的新型候选修饰基因。这些候选基因将在我们未来的研究中得到验证。