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Summary: Background: Equine metabolic syndrome (EMS) is a complex clinical disorder with both environmental and genetic factors contributing to EMS phenotypes. Estimates of heritability determine the proportion of variation in a trait that is attributable to genetics. Objectives: To provide heritability estimates for nine metabolic traits associated with EMS in two high‐risk breeds. Study design: Retrospective cohort study. Methods: High‐density single‐nucleotide polymorphism (SNP) genotype data was used to estimate the heritability (h2SNP) of nine metabolic traits relevant to EMS in a cohort of 264 Welsh ponies and 286 Morgan horses. Traits included measurements of insulin, glucose, non‐esterified fatty acids (NEFA), triglycerides, leptin, adiponectin, ACTH, and glucose (GLU‐OST) and insulin (INS‐OST) following an oral sugar challenge. Results: In Welsh ponies, seven of the nine traits had statistically significant h2SNP estimates that were considered moderately to highly heritable (h2SNP>0.20) including: triglycerides (0.313; s.e. = 0.146), glucose (0.408; s.e. = 0.135), NEFA (0.434; s.e. = 0.136), INS‐OST (0.440; s.e. = 0.148), adiponectin (0.488; s.e. = 0.143), leptin (0.554; s.e. = 0.132) and insulin (0.808; s.e. = 0.108). In Morgans, six of the nine traits had statistically significant h2SNP estimates that were also determined to be moderately to highly heritable including: INS‐OST (0.359; s.e. = 0.185), leptin (0.486; s.e. = 0.177), GLU‐OST (0.566 s.e. = 0.175), insulin (0.592; s.e. = 0.195), NEFA (0.684; s.e. = 0.164), and adiponectin (0.913; s.e. = 0.181). Main limitations: Insufficient population size may have limited power to obtain statistically significant h2SNP estimates for ACTH (both breeds), glucose and triglycerides in Morgans and GLU‐OST in Welsh ponies. Conclusions: This study provides the first concrete evidence of a genetic contribution to key phenotypes associated with EMS. Eight of these nine traits had moderate to high h2SNP estimates in this cohort. These data demonstrate that continued research for identification of the genetic risk factors for EMS phenotypes within and across breeds is warranted. [ABSTRACT FROM AUTHOR]

Summary: Osteochondrosis is a common developmental orthopedic disease characterized by a failure of endochondral ossification. Standardbred horses are recognized as being predisposed to tarsal osteochondrosis. Prior heritability estimates for tarsal osteochondrosis in European Standardbreds and related trotting breeds have been based on pedigree data and range from 17–29%. Here, we report on genetic architecture and heritability based on high‐density genotyping data in a cohort of North American Standardbreds (n = 479) stringently phenotyped for tarsal osteochondrosis. Whole‐genome array genotyping data were imputed to ~2 million single nucleotide polymorphisms (SNPs). SNP‐based heritability of osteochondrosis in this population was explained by 2326 SNPs. The majority of these SNPs (86.6%) had small effects, whereas fewer SNPs had moderate or large effects (10% and 2.9% respectively), which is consistent with a polygenic/complex disease. Heritability was estimated at 0.24 ± 0.16 using two methods of restricted maximum likelihood analysis, as implemented in gcta (with and without a weighted relatedness matrix) and ldak software. Estimates were validated using bootstrapping. Heritability estimates were within the range previously reported and suggest that osteochondrosis is moderately heritable but that a significant portion of disease risk is due to environmental factors and/or genotype × environment interactions. Future identification of the genes/variants that have the most impact on disease risk may allow early recognition of high‐risk individuals. [ABSTRACT FROM AUTHOR]

Summary: Background: Glucose and insulin dynamics may be different in adult and aged horses. Objectives: To determine the effects of age and dietary carbohydrates on glucose and insulin dynamics in healthy horses. Study design: Balanced Latin square with four isocaloric diets: CONTROL (hay plus restricted‐starch‐and‐sugar fortified pellets), STARCH (control plus kibbled corn), FIBER (control plus unmolassed sugar beet pulp/soybean hull pellets) and SUGAR (control plus dextrose powder). Methods: A total of 16 healthy Thoroughbreds and Standardbreds divided into two age groups: ADULT (8.8 ± 2.9 years; n = 8) and AGED (20.6 ± 2.1 years; n = 8). Following dietary adaptation, horses underwent an insulin‐modified frequently sampled intravenous glucose tolerance test (FSIGTT), modified oral sugar test (OST) and dietary meal challenge. Outcome variables included: insulin sensitivity (SI), disposition index (DI), glucose effectiveness (Sg) and acute insulin response to glucose (AIRg) from the FSIGTT; peak glucose, peak insulin, time to peak, area under the curve for glucose (AUCg) and insulin (AUCi) from the OST and dietary meal challenge. Data were analyzed using multivariable linear mixed regression modelling. Results: AIRg was higher in AGED (mean [95% confidence interval]; 582.0 [455.0–709.0]) vs. ADULT (358.0 [224.0–491.0]; P = 0.03). ADULT and AGED horses had a higher SI on STARCH (adult: 3.3 [2.3–4.2]; aged: 2.8 [1.9–3.7]) and SUGAR (adult: 3.4 [2.5–4.3]; aged: 4.0 [3.1–4.9]) diets compared with CONTROL (adult: 2.0 [1.1–2.9], P = 0.029 (starch), P = 0.009 (sugar); aged: 1.4 [0.5–2.2], P = 0.009 (starch), P < 0.001 (sugar)). Feeding a STARCH (adult: 21581.0 [15029.0–28133.0]; aged: 35205.0 [29194.0–41216.0]) or SUGAR (adult: 26050.0 [19885.0–32215.0]; aged: 25720.0 [19770.0–31670.0]) meal resulted in postprandial hyperinsulinaemia (AUCi). Main limitations: Study cohort contained two insulin‐sensitive breeds and no insulin‐resistant breeds. Conclusions: Age and diet should be considered when evaluating glucose and insulin dynamics. [ABSTRACT FROM AUTHOR]

Reasons for performing study Osteochondrosis ( OC) is commonly diagnosed in young Standardbred racehorses but its effect on performance when surgically treated at a young age is still incompletely understood. This is especially true for Standardbred pacers, which are underrepresented in the existing literature. Objective To characterise the short- (2-year-old) and long-term (through 5-year-old) racing performance in Standardbred pacers and trotters after early surgical intervention (<17 months of age) for tarsal OC. Study design Retrospective clinical study. Methods The study population consisted of related, age-matched Standardbred racehorses (n = 278; 151 pacers, 127 trotters) with (n = 133) or without (n = 145) one or more tarsal OC lesions. All OC-affected horses were treated surgically prior to being sold as yearlings. Data obtained from publicly available race records for each horse included starts, wins, finishes in the top 3 (win, place or show), earnings and fastest time. Comparisons between OC-affected and unaffected horses were made for the entire population and within gaits. A smaller related population (n = 94) had these performance measures evaluated for their 2-5-year-old racing seasons. Results Osteochondrosis status was associated with few performance measures. Trotters were at higher risk for lesions of the medial malleolus but lower risk for lesions of the distal intermediate ridge of the tibia than were pacers. Horses with bilateral OC lesions and lateral trochlear ridge ( LTR) lesions started fewer races at 2 years of age than those with unilateral lesions or without LTR lesions. Conclusions Osteochondrosis seemed to have minimal effect on racing performance in this cohort, although horses with bilateral and LTR lesions started fewer races at 2 years. There was evidence for different distribution of OC lesions among pacers and trotters, which should be explored further. Standardbreds undergoing early removal of tarsal OC lesions can be expected to perform equivalently to their unaffected counterparts. [ABSTRACT FROM AUTHOR]

Background: A missense mutation in the GYS1 gene was recently described in horses with polysaccharide storage myopathy (PSSM). Objectives: The first objective was to determine the prevalence of the GYS1 mutation in horses with PSSM from diverse breeds. The second objective was to determine if the prevalence of the GYS1 mutation differed between horses diagnosed with PSSM based on grade 1 (typically amylase-sensitive) or grade 2 (typically amylase-resistant) polysaccharide. Animals: Eight hundred and thirty-one PSSM horses from 36 breeds. Procedures: Horses with PSSM diagnosed by histopathology of skeletal muscle biopsy samples were identified from the Neuromuscular Disease Laboratory database. Eight hundred and thirty-one cases had blood or tissue that was available for DNA isolation; these 831 cases were genotyped for the GYS1 mutation by restriction fragment length polymorphism. Results: The PSSM mutation was identified in horses from 17 different breeds. The prevalence of the GYS1 mutation in PSSM horses was high in Draft- (87%) and Quarter Horse-related breeds (72%) and lower in Warmbloods (18%) and other light horse breeds (24%), when diagnosis was based on grade 2 diagnostic criteria. Overall, the PSSM mutation was present in 16% of grade 1 and 70% of grade 2 PSSM horses. Conclusions and Clinical Importance: GYS1 mutation causes PSSM in diverse breeds and is the predominant form of PSSM in Draft- and Quarter Horse-related breeds. False-positive diagnosis, as well as the possibility of a second glycogenosis in horses with neuromuscular disease (type 2 PSSM), might explain the absence of the GYS1 mutation in horses diagnosed with excessive glycogen accumulation in muscle. [ABSTRACT FROM AUTHOR]

Using these recombination rate estimates, we predicted recombination hotspots with I LDhot i .[8] Finally, we converted recombination rates from 4N SB e sb r to centimorgans with effective population size estimates generated previously.[1] More details are provided in the Data S1. Overall, differences between the updated recombination map and our previous map appear to reflect improvements in the equine genome assembly and provide an improved means for investigating the basis of equine genome structure and function. MAP: Table S1 Differences in physical length, genetic map length, recombination rate and number of predicted hotspots between the previous equine recombination map and the updated map. [Extracted from the article]

Equine Metabolic Syndrome (EMS) is characterized by abnormalities in insulin regulation, increased adiposity and laminitis, and has several similarities to human metabolic syndrome. A large amount of environmental variability in the EMS phenotype is not explained by commonly measured factors (diet, exercise, and season), suggesting that other environmental factors play a role in EMS development. Endocrine disrupting chemicals (EDCs) are associated with metabolic syndrome and other endocrine abnormalities in humans. This led us to hypothesize that EDCs are detectable in horse plasma and play a role in the pathophysiology of EMS. EDCs acting through the aryl hydrocarbon and estrogen receptors, were measured in plasma of 301 horses from 32 farms. The median (range) TEQ (2,3,7,8-TCDD equivalent) and EEQ (17β-estradiol equivalent) were 19.29 pg/g (0.59-536.36) and 10.50 pg/ml (4.35-15000.00), respectively. TEQ was negatively associated with plasma fat extracted and batch analyzed. EEQ was positively associated with pregnancy and batch analyzed, and negatively associated with being male and superfund score ≤100 miles of the farm. Of particular interest, serum glucose and insulin, glucose and insulin post oral sugar challenge, and leptin concentrations were associated with EEQ, and serum triglyceride concentration was associated with TEQ. Overall, we demonstrated that EDCs are present in the plasma of horses and may explain some of the environmental variability in measured EMS phenotypes. This is the first example of EDCs being associated with clinical disease phenotype components in domestic animals., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Diagnosis of equine pituitary pars intermedia dysfunction (PPID) remains a challenge as multiple factors (stress, exercise, and time of year) influence ACTH and cortisol concentrations. To assess endocrine status in a study designed to evaluate the effects of age and diet on glucose and insulin dynamics, we performed thyrotropin-releasing hormone (TRH) stimulation tests and overnight dexamethasone suppression tests in March, May, August, and October on 16 healthy Thoroughbred and Standardbred mares and geldings. Horses were grouped by age: adult (mean ± SD; 8.8 ± 2.9 yr; n = 8) and aged (20.6 ± 2.1 yr; n = 8). None of the horses showed clinical signs (hypertrichosis, regional adiposity, skeletal muscle atrophy, lethargy) of pituitary pars intermedia dysfunction. Horses were randomly assigned to groups of 4, blocked for age, and fed grass hay plus 4 isocaloric concentrate diets (control, starch-rich, fiber-rich, and sugar-rich) using a balanced Latin square design. Data were analyzed using a multivariable linear mixed regression model. Baseline ACTH was significantly higher in aged horses (mean ± standard error of the mean; 60.0 ± 10.7 pg/mL) adapted to the starch-rich diet compared to adult horses (15.7 ± 12.0 pg/mL) on the same diet (P = 0.017). After controlling for age and diet, baseline ACTH concentrations were significantly increased in October (57.7 ± 7.1 pg/mL) compared to March (13.2 ± 7.1 pg/mL; P < 0.001), May (12.4 ± 7.1 pg/mL; P < 0.001), and August (24.2 ± 7.1 pg/mL; P < 0.001), whereas post-TRH ACTH was higher in August (376.6 ± 57.6 pg/mL) and October (370.9 ± 57.5 pg/mL) compared to March (101.9 ± 57.3 pg/mL; P < 0.001) and May (74.5 ± 57.1 pg/mL; P < 0.001). Aged horses had significantly higher post-dexamethasone cortisol on the starch-rich diet (0.6 ± 0.1 μg/dL) compared to the sugar-rich diet (0.2 ± 0.1 μg/dL; P = 0.021). Post-dexamethasone cortisol was significantly higher in October (0.6 ± 0.1 μg/dL) compared to March (0.3 ± 0.1 μg/dL; P = 0.005), May (0.2 ± 0.1 μg/dL; P < 0.001), and August (0.3 ± 0.1 μg/dL; P = 0.004). Breed did not influence ACTH or cortisol measurements. In conclusion, in addition to age and time of year, diet is a potential confounder as animals on a starch-rich diet may be incorrectly diagnosed with pituitary pars intermedia dysfunction., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Equine type 1 polysaccharide storage myopathy (PSSM1) is associated with a missense mutation (R309H) in the glycogen synthase (GYS1) gene, enhanced glycogen synthase (GS) activity and excessive glycogen and amylopectate inclusions in muscle., Methods: Equine muscle biochemical and recombinant enzyme kinetic assays in vitro and homology modelling in silico, were used to investigate the hypothesis that higher GS activity in affected horse muscle is caused by higher GS expression, dysregulation, or constitutive activation via a conformational change., Results: PSSM1-affected horse muscle had significantly higher glycogen content than control horse muscle despite no difference in GS expression. GS activity was significantly higher in muscle from homozygous mutants than from heterozygote and control horses, in the absence and presence of the allosteric regulator, glucose 6 phosphate (G6P). Muscle from homozygous mutant horses also had significantly increased GS phosphorylation at sites 2+2a and significantly higher AMPKα1 (an upstream kinase) expression than controls, likely reflecting a physiological attempt to reduce GS enzyme activity. Recombinant mutant GS was highly active with a considerably lower K m for UDP-glucose, in the presence and absence of G6P, when compared to wild type GS, and despite its phosphorylation., Conclusions: Elevated activity of the mutant enzyme is associated with ineffective regulation via phosphorylation rendering it constitutively active. Modelling suggested that the mutation disrupts a salt bridge that normally stabilises the basal state, shifting the equilibrium to the enzyme's active state., General Significance: This study explains the gain of function pathogenesis in this highly prevalent polyglucosan myopathy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Both graying and melanoma formation in horses have recently been linked to a duplication in the STX17 gene. This duplication, as well as a mutation in the ASIP gene that increases MC1R pathway signaling, affects melanoma risk and severity in gray horses., Objective: To determine if melanoma susceptibility in gray Quarter Horses (QH) is lower than gray horses from other breeds because of decreased MC1R signaling resulting from a high incidence of the MC1R chestnut coat color allele in the QH population., Animals: A total of 335 gray QH with and without dermal melanomas., Methods: Blood or hair root samples were collected from all horses for DNA extraction and genotyping for STX17, ASIP, and MC1R genotypes. Age, sex, and external melanoma presence and grade were recorded. The effect of age and genotype on melanoma presence and severity was evaluated by candidate gene association., Results: Melanoma prevalence (16%) and grade (0.35) in this QH cohort was lower than that reported in other breeds. Age was significantly associated with melanoma prevalence (P = 5.28 × 10(-11)) and severity (P = 2.2 × 10(-13)). No significant effect of MC1R genotype on melanoma prevalence or severity was identified. An effect of ASIP genotype on melanoma risk was not detected. Low STX17 homozygosity precluded evaluation of the gray allele effect., Conclusion and Clinical Importance: Melanoma prevalence and severity is lower in this population of gray QH than what is reported in other breeds. This could be because of the infrequent STX17 homozygosity, a mitigating effect of the MC1R mutation on ASIP potentiation of melanoma, other genes in the MC1R signaling pathway, or differences in breed genetic background., (Copyright © 2013 by the American College of Veterinary Internal Medicine.)

In this study we examined a family of Quarter Horses with Polysaccharide Storage Myopathy (PSSM) with a dominant mutation in the skeletal muscle glycogen synthase (GYS1) gene. A subset of horses within this family had a more severe and occasionally fatal PSSM phenotype. The purpose of this study was to identify a modifying gene(s) for the severe clinical phenotype. A genetic association analysis was used to identify RYR1 as a candidate modifying gene. A rare, known equine RYR1 mutation, associated with malignant hyperthermia (MH), was found to segregate in this GYS1 PSSM family. Retrospective analysis of patient records (n=179) demonstrated that horses with both the GYS1 and RYR1 mutations had a more severe clinical phenotype than horses with the GYS1 mutation alone. A treadmill trial (n=8) showed that serum creatine kinase activity was higher and exercise intolerance greater in horses with both mutations compared to the GYS1 mutation alone.