Transcriptomic and genetic profiling in a spontaneous non-human primate model of hypertrophic cardiomyopathy and sudden cardiac death
Abstract 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 rema...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-12-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-024-82770-4 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846101214079483904 |
|---|---|
| author | Victor N. Rivas Michael W. Vandewege Yu Ueda Joanna L. Kaplan JRachel Reader Jeffrey A. Roberts Joshua A. Stern |
| author_facet | Victor N. Rivas Michael W. Vandewege Yu Ueda Joanna L. Kaplan JRachel Reader Jeffrey A. Roberts Joshua A. Stern |
| author_sort | Victor N. Rivas |
| collection | DOAJ |
| description | Abstract 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 Adjusted-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. |
| format | Article |
| id | doaj-art-800c7b21dac84ef9b32692c42b5a1cad |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-800c7b21dac84ef9b32692c42b5a1cad2024-12-29T12:22:52ZengNature PortfolioScientific Reports2045-23222024-12-0114111910.1038/s41598-024-82770-4Transcriptomic and genetic profiling in a spontaneous non-human primate model of hypertrophic cardiomyopathy and sudden cardiac deathVictor N. Rivas0Michael W. Vandewege1Yu Ueda2Joanna L. Kaplan3JRachel Reader4Jeffrey A. Roberts5Joshua A. Stern6Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State UniversityDepartment of Clinical Sciences, College of Veterinary Medicine, North Carolina State UniversityDepartment of Clinical Sciences, College of Veterinary Medicine, North Carolina State UniversityDepartment of Medicine & Epidemiology, School of Veterinary Medicine, University of California-DavisCalifornia National Primate Research Center, University of California-DavisCalifornia National Primate Research Center, University of California-DavisDepartment of Clinical Sciences, College of Veterinary Medicine, North Carolina State UniversityAbstract 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 Adjusted-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.https://doi.org/10.1038/s41598-024-82770-4Whole-genome sequencingRNA-sequencingMulti-omicsMonkeyLarge-animal modelArrythmia |
| spellingShingle | Victor N. Rivas Michael W. Vandewege Yu Ueda Joanna L. Kaplan JRachel Reader Jeffrey A. Roberts Joshua A. Stern Transcriptomic and genetic profiling in a spontaneous non-human primate model of hypertrophic cardiomyopathy and sudden cardiac death Scientific Reports Whole-genome sequencing RNA-sequencing Multi-omics Monkey Large-animal model Arrythmia |
| title | Transcriptomic and genetic profiling in a spontaneous non-human primate model of hypertrophic cardiomyopathy and sudden cardiac death |
| title_full | Transcriptomic and genetic profiling in a spontaneous non-human primate model of hypertrophic cardiomyopathy and sudden cardiac death |
| title_fullStr | Transcriptomic and genetic profiling in a spontaneous non-human primate model of hypertrophic cardiomyopathy and sudden cardiac death |
| title_full_unstemmed | Transcriptomic and genetic profiling in a spontaneous non-human primate model of hypertrophic cardiomyopathy and sudden cardiac death |
| title_short | Transcriptomic and genetic profiling in a spontaneous non-human primate model of hypertrophic cardiomyopathy and sudden cardiac death |
| title_sort | transcriptomic and genetic profiling in a spontaneous non human primate model of hypertrophic cardiomyopathy and sudden cardiac death |
| topic | Whole-genome sequencing RNA-sequencing Multi-omics Monkey Large-animal model Arrythmia |
| url | https://doi.org/10.1038/s41598-024-82770-4 |
| work_keys_str_mv | AT victornrivas transcriptomicandgeneticprofilinginaspontaneousnonhumanprimatemodelofhypertrophiccardiomyopathyandsuddencardiacdeath AT michaelwvandewege transcriptomicandgeneticprofilinginaspontaneousnonhumanprimatemodelofhypertrophiccardiomyopathyandsuddencardiacdeath AT yuueda transcriptomicandgeneticprofilinginaspontaneousnonhumanprimatemodelofhypertrophiccardiomyopathyandsuddencardiacdeath AT joannalkaplan transcriptomicandgeneticprofilinginaspontaneousnonhumanprimatemodelofhypertrophiccardiomyopathyandsuddencardiacdeath AT jrachelreader transcriptomicandgeneticprofilinginaspontaneousnonhumanprimatemodelofhypertrophiccardiomyopathyandsuddencardiacdeath AT jeffreyaroberts transcriptomicandgeneticprofilinginaspontaneousnonhumanprimatemodelofhypertrophiccardiomyopathyandsuddencardiacdeath AT joshuaastern transcriptomicandgeneticprofilinginaspontaneousnonhumanprimatemodelofhypertrophiccardiomyopathyandsuddencardiacdeath |