Palomino Lago Esther, Baird Arabella, Blott Sarah C, McPhail Rhona E, Ross Amy C, Durward-Akhurst Sian A, Guest Deborah J
Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield AL9 7TA, UK.
Animal Health Trust, Lanwades Park, Kentford, Newmarket CB8 7UU, UK.
Animals (Basel). 2023 Dec 28;14(1):116. doi: 10.3390/ani14010116.
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.
骨骼超负荷导致的骨折是纯种赛马实施安乐死的主要原因。致命骨折的风险已被证明受环境和遗传因素的影响，但迄今为止，尚未确定导致骨折的具体遗传机制。在本研究中，我们利用全基因组多基因风险评分建立了一个体外细胞系统，以研究骨折遗传风险高和低的马匹的骨基因调控。候选基因表达分析显示，高风险和低风险马匹来源的成骨细胞中，[具体基因1]和[具体基因2]基因存在差异表达。对两例骨折病例和两匹对照马进行全基因组测序，发现[基因名称]上游存在一个单核苷酸多态性（SNP），在更大的队列中证实该SNP与骨折显著相关。生物信息学工具预测，该SNP可能影响转录因子SOX11的结合。基因调控表明SOX11在[基因名称]上游，且该区域与核蛋白结合。此外，荧光素酶检测表明，包含该SNP的区域具有启动子活性。然而，该SNP的具体作用取决于细胞更广泛的遗传背景，这表明其他因素可能也参与调控[基因名称]的表达。总之，我们鉴定出一个与骨折风险显著相关的新型SNP，并为[基因名称]基因的调控提供了新的见解。
