Division of Cardiovascular Diseases, Department of Medicine, Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, United States of America.
Division of Cardiovascular Diseases, Department of Medicine, Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, United States of America.
Int J Cardiol. 2021 May 1;330:135-141. doi: 10.1016/j.ijcard.2021.01.047. Epub 2021 Jan 30.
Clinical phenotypes of hypertrophic cardiomyopathy (HCM) vary greatly even among patients with the same gene mutations. This variability is largely regulated by unidentified modifier loci. The purpose of the study is to identify modifier genes for cardiac fibrosis-a major phenotype of HCM-using the BXD family, a murine cohort.
The relative severity of cardiac fibrosis was estimated by quantitation of cardiac collagen volume fraction (CCVF) across 66 members of the BXD family. Quantitative trait locus (QTL) mapping for cardiac fibrosis was done using GeneNetwork. Candidate modifier loci and genes associated with fibrosis were prioritized based on an explicit scoring system. Networks of correlation between fibrosis and cardiac transcriptomes were evaluated to generate causal models of disease susceptibility.
CCVF levels varied greatly within this family. Interval mapping identified a significant CCVF-related QTL on chromosome (Chr) 2 in males, and a significant QTL on Chr 4 Mb in females. The scoring system highlighted two strong candidate genes in the Chr 2 locus-Nek6 and Nr6a1. Both genes are highly expressed in the heart. Cardiac Nek6 mRNA levels are significantly correlated with CCVF. Nipsnap3b and Fktn are lead candidate genes for the Chr 4 locus, and both are also highly expressed in heart. Cardiac Nipsnap3b gene expression correlates well with CCVF.
Our study demonstrated that candidate modifier genes of cardiac fibrosis phenotype in HCM are different in males and females. Nek6 and Nr6a1 are strong candidates in males, while Nipsnap3b and Fktn are top candidates in females.
即使在携带相同基因突变的患者中，肥厚型心肌病（HCM）的临床表型也存在很大差异。这种变异性在很大程度上受到未识别的修饰基因座调控。本研究旨在利用 BXD 家族这一鼠群，鉴定心脏纤维化（HCM 的主要表型之一）的修饰基因。
通过对 BXD 家族的 66 名成员的心脏胶原容积分数（CCVF）进行定量，评估心脏纤维化的相对严重程度。使用 GeneNetwork 对心脏纤维化进行数量性状基因座（QTL）定位。根据明确的评分系统，优先考虑与纤维化相关的候选修饰基因座和基因。评估纤维化与心脏转录组之间的相关性网络，以生成疾病易感性的因果模型。
该家族内的 CCVF 水平差异很大。区间映射在雄性中确定了一个与 CCVF 相关的显著 QTL 位于第 2 号染色体，在雌性中确定了一个位于第 4 号染色体 4Mb 处的显著 QTL。评分系统突出了第 2 号染色体位置上的两个强有力的候选基因-Nek6 和 Nr6a1。这两个基因在心脏中均高度表达。心脏 Nek6 mRNA 水平与 CCVF 显著相关。Nipsnap3b 和 Fktn 是第 4 号染色体位置的主要候选基因，在心脏中也高度表达。心脏 Nipsnap3b 基因表达与 CCVF 相关性良好。
我们的研究表明，HCM 心脏纤维化表型的候选修饰基因在男性和女性中是不同的。Nek6 和 Nr6a1 是男性中的强候选基因，而 Nipsnap3b 和 Fktn 是女性中的顶级候选基因。
