Identification of osteopontin as a positional and functional candidate gene for cardiac hypertrophy in the SHRSP rat

Trivett, C.; Martin, T. P.; Asirvatham, A.; Foote, K.; Monkeviciute, A.; Beattie, W.; Loughrey, C. M.; McClure, J. D.; Dominiczak, A. F.; Graham, D.; McBride, M. W.

doi:10.64898/2026.08.24.746886

bioRxiv · 10.64898/2026.08.24.746886

Identification of osteopontin as a positional and functional candidate gene for cardiac hypertrophy in the SHRSP rat

Trivett, C.·Martin, T. P.·Asirvatham, A.·Foote, K.·Monkeviciute, A.·Beattie, W.·Loughrey, C. M.·McClure, J. D.·Dominiczak, A. F.·Graham, D.·McBride, M. W.

View original source ↗Export metadata ↓

Abstract

Left ventricular hypertrophy, common in cardiometabolic and renal disease, is a major risk factor for cardiovascular morbidity and mortality. Left ventricular mass is a highly heritable, polygenic trait. Linkage studies in WKY and SHRSP rats have identified a quantitative trait locus for left ventricular mass index on chromosome 14. Congenic strains, where trait-associated genetic loci are introduced into a control strain, can identify causal genetic mediators relevant to human disease. Chromosome 14 congenic (WKY.SPGla14a), WKY, and SHRSP strains underwent cardiac phenotyping and transcriptome profiling at; 1-3 days (neonate), 5 weeks, and 16-weeks. Compared to WKY, LVMI was significantly increased in SHRSP and WKY.SPGla14a at 5 weeks (LVMISHRSP-WKY=0.26g/kg, LVMIWKY.SPGla14a-WKY=0.30g/kg), prior to measured hypertension in this model. SHRSP blood pressure was significantly greater than WKY.SPGla14a, and WKY from 12-20 weeks (AUCdiff=497 vs WKY, AUCdiff=412 vs WKY.SPGla14a). Cardiac transcriptome analysis of neonate, 5-week, and 16-week hearts identified significantly increased expression of secreted phosphoprotein 1 (Spp1/osteopontin) in SHRSP and WKY.SPGla14a compared to WKY, which is positioned within the transferred congenic region. Overexpression of Spp1 mRNA significantly increased H9c2 cell size and was shown to be transferred in small extracellular vesicles (sEV). Overexpression of Spp1 in neonatal chromosome 14 congenic and SHRSP strains preceded development of increased cardiac mass and onset of hypertension. The congenic strategy identified Spp1 as a positional and functional candidate gene determining increased LVMI in the SHRSP model of human cardiovascular disease.

Explore related subjects

genetics Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Trivett, C., Martin, T. P., Asirvatham, A., Foote, K., Monkeviciute, A., Beattie, W., Loughrey, C. M., McClure, J. D., Dominiczak, A. F., Graham, D., McBride, M. W.. 2026-08-27. Identification of osteopontin as a positional and functional candidate gene for cardiac hypertrophy in the SHRSP rat. https://doi.org/10.64898/2026.08.24.746886

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Large language model-based bibliometric evaluation of population descriptors in human genetics

As the use of population descriptors such as race, ethnicity, and ancestry have become increasingly common in modern genetics research, there have been growing calls to critically examine their use. Most notably, in 2023, the National Academies of Science, Engineering, and Medicine (NASEM) published a report titled Using Population Descriptors in Genetics and Genomics Research: A New Framework for an Evolving Field, which included eight specific and actionable recommendations for researchers to implement the ethical and accurate use of population descriptors in genetic research. Here, we use the 2023 NASEM report as a benchmark to analyze the use of population descriptors in genome-wide association studies (GWAS). We develop a general toolkit for large language model-based bibliometrics, operationalize the report's recommendations into an evaluation framework, and apply this framework to evaluate all 4,007 papers from the GWAS Catalog published between 2007 and 2025 with full text available on PubMedCentral. We find significant improvements in adherence to NASEM report recommendations over time. However, most improvements predate the publication of the NASEM report itself, suggesting the report functioned primarily as a synthesis of existing best practices rather than a catalyst for change. We conclude by highlighting opportunities for growth in the field of human genetics.

genetics↗

bioRxiv2026

Mitigating biases of rescaling in forward-in-time population genetic simulations

Forward-in-time population genetic simulations are widely used in evolutionary analyses, but simulating large populations and long genomic regions remains computationally demanding. To reduce this cost, parameter rescaling is widely employed, in which the original evolutionary process is approximated by one with a smaller population size and fewer generations. Recently, several studies using the SLiM simulator have raised concerns about the accuracy of this rescaling approach. In this study, we show that many of the biases reported in these studies can be mitigated by using a different simulation algorithm. These results reveal that the accuracy of parameter rescaling depends on how well the simulation algorithm preserves diffusion-limit properties under rescaling.

genetics↗

bioRxiv2026

OPA1 controls mitochondrial dysfunction-driven liver fibrosis in MASLD

Progressive hepatic fibrosis is the principal determinant of morbidity and mortality in metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH). Mitochondrial dysfunction is a hallmark of MASH, and the release of mitochondrial damage-associated molecular patterns (mito-DAMPs) from injured hepatocytes can promote fibrosis. However, how mitochondrial dynamics and quality control shape the fibrotic response in MASLD/MASH remains unclear. Here, through large-scale genomic analyses of mitochondrial genes governing mitophagy, fusion and fission in human MASLD, with a power-equivalent sample size of approximately 700,000 individuals, we identify a strong association between hepatic fibrosis and the mitochondrial fusion factor dynamin-like GTPase optic atrophy 1 (OPA1). OPA1 transcripts and protein abundance in the liver epithelium were progressively dysregulated with advancing fibrosis. In mice, hepatocyte-specific OPA1 loss alone was sufficient to induce hepatic stellate cell activation and fibrosis in zone 3, promoted the release of mito-DAMPs into the circulation and exacerbated fibrosis in experimental MASH. These findings identify OPA1 as a central regulator of the hepatic fibrotic response and connect defective mitochondrial homeostasis to mito-DAMP release, hepatic stellate cell activation and fibrosis in MASLD.

genetics↗