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Animals : an open access journal from MDPI2023; 14(1); 116; doi: 10.3390/ani14010116

A Functional Single-Nucleotide Polymorphism Upstream of the Collagen Type III Gene Is Associated with Catastrophic Fracture Risk in Thoroughbred Horses.

Abstract: Fractures caused by bone overloading are a leading cause of euthanasia in Thoroughbred racehorses. The risk of fatal fracture has been shown to be influenced by both environmental and genetic factors but, to date, no specific genetic mechanisms underpinning fractures have been identified. In this study, we utilised a genome-wide polygenic risk score to establish an in vitro cell system to study bone gene regulation in horses at high and low genetic risk of fracture. Candidate gene expression analysis revealed differential expression of and genes in osteoblasts derived from high- and low-risk horses. Whole-genome sequencing of two fracture cases and two control horses revealed a single-nucleotide polymorphism (SNP) upstream of that was confirmed in a larger cohort to be significantly associated with fractures. Bioinformatics tools predicted that this SNP may impact the binding of the transcription factor SOX11. Gene modulation demonstrated SOX11 is upstream of , and the region binds to nuclear proteins. Furthermore, luciferase assays demonstrated that the region containing the SNP has promoter activity. However, the specific effect of the SNP depends on the broader genetic background of the cells and suggests other factors may also be involved in regulating expression. In conclusion, we have identified a novel SNP that is significantly associated with fracture risk and provide new insights into the regulation of the gene.
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Publication Date: 2023-12-28 PubMed ID: 38200847PubMed Central: PMC10778232DOI: 10.3390/ani14010116Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article discusses a detected variation in a single DNA building block—referred to as Single Nucleotide Polymorphism (SNP)—in Thoroughbred horses linked to a higher risk of catastrophic fractures. This SNP is positioned upstream of the COL3A1 gene, which is responsible for the production of a type of collagen stitched into bones and cartilage. The presence of SNP is believed to interfere with the regulatory activities of the SOX11 transcription factor, thus affecting the function of COL3A1 and increasing the fracture risk.

Genome-Wide Polygenic Risk Score

  • The researchers employed a genome-wide polygenic risk score for their investigation. This is a method that focuses on associations between genetic variations spread across the entire genome and certain characteristics or diseases—in this case, the likelihood of fracture in Thoroughbred horses.

Candidate Gene Expression Analysis

  • They conducted a candidate gene expression analysis on genes in osteoblasts—cells responsible for bone formation—sourced from high-and-low risk horses. The identified COL3A1 gene showed distinct expression levels in those cells.

Identifying the SNP

  • By examining the DNA data from two fracture cases and two control horses in this study, the identified SNP was pinpointed to be upstream of the COL3A1 gene.
  • Further investigations confirmed that this specific SNP is significantly linked with fractures. This likely impacts the binding of the SOX11 transcription factor that regulates the COL3A1 gene.

Effects of the SNP

  • SOX11’s position has been found to be upstream of the COL3A1 gene. It means that it potentially influences the genetic expression of COL3A1.
  • The region containing this SNP demonstrated promoter activity, which further underlines its influence on the activity of genes downstream.
  • However, the specific implications of this SNP seem to hinge on a broader genetic context. It suggests that other factors too play a role in controlling COL3A1 expression and consequently, the susceptibility to fractures.

Conclusion

  • This investigation has marked the discovery of a new SNP that has substantial association with the risk of fractures in Thoroughbred horses.
  • Further, it has provided new insights into the regulation of the COL3A1 gene which is crucial for understanding the genetic basis of catastrophic bone injuries.

Cite This Article

APA
Palomino Lago E, Baird A, Blott SC, McPhail RE, Ross AC, Durward-Akhurst SA, Guest DJ. (2023). A Functional Single-Nucleotide Polymorphism Upstream of the Collagen Type III Gene Is Associated with Catastrophic Fracture Risk in Thoroughbred Horses. Animals (Basel), 14(1), 116. https://doi.org/10.3390/ani14010116

Publication

Animals : an open access journal from MDPI
ISSN: 2076-2615
NlmUniqueID: 101635614
Country: Switzerland
Language: English
Volume: 14
Issue: 1
PII: 116

Researcher Affiliations

Palomino Lago, Esther
  • Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield AL9 7TA, UK.
Baird, Arabella
  • Animal Health Trust, Lanwades Park, Kentford, Newmarket CB8 7UU, UK.
Blott, Sarah C
  • School of Veterinary Medicine and Science, University of Nottingham, Nottingham LE12 5RD, UK.
McPhail, Rhona E
  • Animal Health Trust, Lanwades Park, Kentford, Newmarket CB8 7UU, UK.
Ross, Amy C
  • Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield AL9 7TA, UK.
Durward-Akhurst, Sian A
  • Department of Veterinary Clinical Sciences, University of Minnesota, Saint Paul, MN 55108, USA.
Guest, Deborah J
  • Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield AL9 7TA, UK.

Grant Funding

  • vet/prj/792 / Horserace Betting Levy Board
  • N/A / Anne Duchess of Westminster Charitable Trust
  • N/A / Alborada Trust

Conflict of Interest Statement

E. Palomino Lago and D.J. Guest are affiliated with The Royal Veterinary College, which holds patent WO 2015/019097 “Predictive Method for Bone Fracture Risk in Horses” in relation to this work. This patent claims a method of predicting fracture risk in horses using one or more genetic variations from within the associated region on ECA18. None of the other authors have any other competing interests to declare.

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Citations

This article has been cited 2 times.
  1. Martinez-Saez L, Marín-García PJ, Llobat ML. Osteochondrosis in horses: An overview of genetic and other factors. Equine Vet J 2026 Jan;58(1):6-19.
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  2. Palomino Lago E, Ross AKC, McClellan A, Guest DJ. Identification of a global gene expression signature associated with the genetic risk of catastrophic fracture in iPSC-derived osteoblasts from Thoroughbred horses. Anim Genet 2025 Feb;56(1):e13504.
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