Rivas Victor N, Vandewege Michael W, Ueda Yu, Kaplan Joanna L, Reader JRachel, Roberts Jeffrey A, Stern Joshua A
Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Dr, Raleigh, NC, 27607, USA.
Department of Medicine & Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA, USA.
Sci Rep. 2024 Dec 28;14(1):31344. doi: 10.1038/s41598-024-82770-4.
Hypertrophic cardiomyopathy (HCM) afflicts humans, cats, pigs, and rhesus macaques. Disease sequelae include congestive heart failure, thromboembolism, and sudden cardiac death (SCD). Sarcomeric mutations explain some human and cat cases, however, the molecular basis in rhesus macaques remains unknown. RNA-Seq of the LV tissues of five HCM-affected and seven healthy control rhesus macaques was employed for differential transcriptomic analyses. DNA from 15 severely HCM-affected and 21 healthy geriatric rhesus macaques were selected for whole-genome sequencing. A genome-wide association study (GWAS) of disease status and SCD outcome was performed. 614 down- and 1,065 upregulated differentially expressed genes (DEGs) were identified between groups. The top DEG (MAFF) was overexpressed in affected animals (log2FoldChange = 4.71; P-value = 1.14E-133). Channelopathy-associated enriched terms were identified in ~ 57% of downregulated DEGs providing transcriptomic evidence of hypertrophic and arrhythmic disease processes. For GWAS, no putative variant withstood segregation. Polygenic modeling analysis resulted in poor prediction power and burden testing could not explain HCM by an association of multiple variants in any gene. Neither single nor compound genetic variant(s), or identified polygenic profile, suggest complex genotype-phenotype interactions in rhesus macaques. Brought forth is an established dataset of robustly phenotyped rhesus macaques as an open-access resource for future cardiovascular disease genetic studies.
肥厚型心肌病（HCM）在人类、猫、猪和恒河猴中均有发生。疾病后遗症包括充血性心力衰竭、血栓栓塞和心源性猝死（SCD）。肌节突变可解释部分人类和猫的病例，然而，恒河猴的分子基础仍不清楚。对五只受HCM影响的恒河猴和七只健康对照恒河猴的左心室组织进行RNA测序，用于差异转录组分析。从15只严重受HCM影响的老年恒河猴和21只健康老年恒河猴中提取DNA进行全基因组测序。对疾病状态和SCD结局进行全基因组关联研究（GWAS）。两组之间共鉴定出614个下调和1065个上调的差异表达基因（DEG）。顶级DEG（MAFF）在受影响动物中过表达（log2倍变化=4.71；P值=1.14E-133）。在约57%的下调DEG中鉴定出与通道病相关的富集术语，为肥厚性和心律失常性疾病过程提供了转录组学证据。对于GWAS，没有推定的变异能够经受住分离检验。多基因建模分析导致预测能力较差，负担测试无法通过任何基因中多个变异的关联来解释HCM。无论是单个还是复合遗传变异，或已鉴定的多基因图谱，均未表明恒河猴存在复杂的基因型-表型相互作用。本文提出了一个已建立的恒河猴强表型数据集，作为未来心血管疾病遗传研究的开放获取资源。
