A review of investigated risk factors for developing equine recurrent uveitis.

Equine recurrent uveitis (ERU) is an ocular inflammatory disease that can be difficult to manage clinically. As such, it is the leading cause of bilateral blindness for horses. ERU is suspected to have a complex autoimmune etiology with both environmental and genetic risk factors contributing to onset and disease progression in some or all cases. Work in recent years has aimed at unraveling the primary triggers, such as infectious agents and inherited breed-specific risk factors, for disease onset, persistence, and progression. This review has aimed at encompassing those factors that have been associated, implicated, or substantiated as contributors to ERU, as well as identifying areas for which additional knowledge is needed to better understand risk for disease onset and progression. A greater understanding of the risk factors for ERU will enable earlier detection and better prognosis through prevention and new therapeutics.

Risk factors for insidious uveitis in the Knabstrupper breed.

BACKGROUND: Equine recurrent uveitis (ERU) is the leading cause of blindness for horses; previous research implicated the leopard complex spotting allele (LP) as a genetic risk factor for insidious uveitis in the Appaloosa. There is limited information about risk in the Knabstrupper. OBJECTIVE: To evaluate clinical manifestations, disease frequency and potential risk factors for ERU in Knabstrupper horses. STUDY DESIGN: Cross-sectional study. METHODS: Ocular examinations were performed on 116 horses, and based on identified anomalies, horses were classified as suspect, ERU-affected or having no clinical signs. Microagglutination testing (MAT) of serum assessed exposure to Leptospira spp. Clinical signs, age, sex, base colour, coat pattern, LP and PATN1 genotypes, percent white at birth, progressive roaning and Leptospira were assessed as risk factors using multivariable exact logistic regression, accounting for clustering at the barn level. Additionally, a pedigree analysis was performed (n = 20 cases and 21 controls), and coefficients of coancestry (CC) and inbreeding were calculated. RESULTS: Prevalence of insidious uveitis in this sample of Knabstruppers was 20.7%. Similar to findings for Appaloosas, LP homozygotes had higher odds of uveitis compared with true solid (N/N) horses (LP/LP OR = 7.64, 95% CI [0.8 to +INF], p = 0.04) and age was also identified as a risk factor. After accounting for LP, the 16-20 age group had higher odds compared with the youngest group (OR = 13.36, 95% CI [1.4-213.4], p = 0.009). The distributions of average CC were significantly different between cases and controls (p = 0.01). MAIN LIMITATIONS: A relatively small sample size decreased the power for detecting additional associations. The progressive nature of insidious uveitis may have prevented identification of younger affected horses. CONCLUSIONS: Our data support genotyping for LP to assess risk of ERU in Knabstruppers. Additional studies are necessary to develop more robust risk models across LP breeds for earlier detection and improved clinical management.

Heritability of insidious uveitis in Appaloosa horses.

Equine recurrent uveitis (ERU) is a blinding ocular disorder among horses, and the Appaloosa horse breed is disproportionally affected by a chronic form of this intraocular inflammatory disease known as insidious uveitis. Strong breed predisposition and previous investigations suggest that there is a genetic component to the pathology of insidious uveitis among Appaloosa horses; however, no estimates of the heritability of the disease have previously been determined. This study aimed to characterize the genetic underpinning of the disease by estimating the heritability for insidious uveitis among Appaloosas. After combining two genotyping array datasets from the Illumina Equine SNP70 BeadChip and the Axiom Equine 670 K Genotyping Array, heritability was estimated for 59 affected and 83 unaffected horses using both restricted maximum likelihood (REML) and phenotype correlation - genotype correlation solvers from the linkage disequilibrium adjusted kinship software. Based on previous research, age and sex were used as covariates, and the locus responsible for the characteristic Appaloosa coat pattern (LP), previously associated with ERU risk, was included as a fixed effect ('top predictor'). Using prevalence values from 0.05 to 0.42, the heritability estimate for insidious uveitis ranged from 0.95 (SE = 0.14) to 1.74 (SE = 0.25) with LP contributing 0.16-0.33 to the estimate. This study suggests that insidious uveitis is highly heritable (REML 95% CI, h2  = 0.68-1.0) and additional loci outside of LP are contributing to the genetic risk for insidious uveitis for Appaloosas. Once identified, these other genetic factors may lead to new disease mitigation efforts in veterinary care and breeding practices.

Prediction of histone post-translational modification patterns based on nascent transcription data.

The role of histone modifications in transcription remains incompletely understood. Here, we examine the relationship between histone modifications and transcription using experimental perturbations combined with sensitive machine-learning tools. Transcription predicted the variation in active histone marks and complex chromatin states, like bivalent promoters, down to single-nucleosome resolution and at an accuracy that rivaled the correspondence between independent ChIP-seq experiments. Blocking transcription rapidly removed two punctate marks, H3K4me3 and H3K27ac, from chromatin indicating that transcription is required for active histone modifications. Transcription was also required for maintenance of H3K27me3, consistent with a role for RNA in recruiting PRC2. A subset of DNase-I-hypersensitive sites were refractory to prediction, precluding models where transcription initiates pervasively at any open chromatin. Our results, in combination with past literature, support a model in which active histone modifications serve a supportive, rather than an essential regulatory, role in transcription.

Generation of a Biobank From Two Adult Thoroughbred Stallions for the Functional Annotation of Animal Genomes Initiative.

Following the successful creation of a biobank from two adult Thoroughbred mares, this study aimed to recapitulate sample collection in two adult Thoroughbred stallions as part of the Functional Annotation of the Animal Genome (FAANG) initiative. Both stallions underwent thorough physical, lameness, neurologic, and ophthalmic (including electroretinography) examinations prior to humane euthanasia. Epididymal sperm was recovered from both stallions immediately postmortem and cryopreserved. Aseptically collected full thickness skin biopsies were used to isolate, culture and cryopreserve dermal fibroblasts. Serum, plasma, cerebrospinal fluid, urine, and gastrointestinal content from various locations were collected and cryopreserved. Under guidance of a board-certified veterinary anatomic pathologist, 102 representative tissue samples were collected from both horses. Whole tissue samples were flash-frozen and prioritized tissues had nuclei isolated and cryopreserved. Spatially contemporaneous samples of each tissue were submitted for histologic examination. Antemortem and gross pathologic examination revealed mild abnormalities in both stallions. One stallion (ECA_UCD_AH3) had unilateral thoracic limb lameness and bilateral chorioretinal scars. The second stallion (ECA_UCD_AH4) had subtle symmetrical pelvic limb ataxia, symmetrical prostatomegally, and moderate gastrointestinal nematodiasis. DNA from each was whole-genome sequenced and genotyped using the GGP Equine 70K SNP array. The genomic resources and banked biological samples from these animals augments the existing resource available to the equine genomics community. Importantly we may now improve the resolution of tissue-specific gene regulation as affected by sex, as well as add sex-specific tissues and gametes.

Risk factors for equine recurrent uveitis in a population of Appaloosa horses in western Canada.

OBJECTIVE: To characterize clinical manifestations, measure frequency, and evaluate risk factors for equine recurrent uveitis (ERU) in Appaloosa horses in western Canada. ANIMALS: 145 Appaloosa horses. PROCEDURES: Ophthalmic examinations were completed and eyes were classified as having no or mild clinical signs, or moderate, or severe damage from ERU. Clinical signs, age, sex, base coat color, and pattern were recorded. Whole blood and/or mane hair follicles were collected for DNA extraction, and all horses were tested for the leopard complex (LP) spotting pattern allele. Pedigree analysis was completed on affected and unaffected horses, and coefficients of coancestry (CC) and inbreeding (COI) were determined. RESULTS: Equine recurrent uveitis was confirmed in 20 (14%) horses. The mean age of affected horses was 12.3 years (±5.3; range 3-25). Age was a significant risk factor for ERU diagnosis (ORyear  = 1.15) and classification (ORyear  = 1.19). The fewspot coat pattern was significantly associated with increased risk for ERU compared to horses that were minimally patterned or true solids. The LP/LP genotype was at a significantly greater risk for ERU compared to lp/lp (OR = 19.4) and LP/lp (OR = 6.37). Classification of ERU was greater in the LP/LP genotype compared to LP/lp. Affected horses had an average CC of 0.066, and there was a significant difference in the distribution of CC for affected horses versus the control group (P = .021). One affected horse was the sire or grandsire of nine other affected. CONCLUSIONS: Age, coat pattern, and genetics are major risk factors for the diagnosis and classification of ERU in the Appaloosa.