Recurrent airway obstruction (RAO), or heaves, is a naturally occurring asthma-like disease that is related to sensitisation and exposure to mouldy hay and has a familial basis with a complex mode of inheritance. A genome-wide scanning approach using two half-sibling families was taken in order to locate the chromosome regions that contribute to the inherited component of this condition in these families. Initially, a panel of 250 microsatellite markers, which were chosen as a well-spaced, polymorphic selection covering the 31 equine autosomes, was used to genotype the two half-sibling families, which comprised in total 239 Warmblood horses. Subsequently, supplementary markers were added for a total of 315 genotyped markers. Each half-sibling family is focused around a severely RAO-affected stallion, and the phenotype of each individual was assessed for RAO and related signs, namely, breathing effort at rest, breathing effort at work, coughing, and nasal discharge, using an owner-based questionnaire. Analysis using a regression method for half-sibling family structures was performed using RAO and each of the composite clinical signs separately; two chromosome regions (on ECA13 and ECA15) showed a genome-wide significant association with RAO at P < 0.05. An additional 11 chromosome regions showed a more modest association. This is the first publication that describes the mapping of genetic loci involved in RAO. Several candidate genes are located in these regions, a number of which are interleukins. These are important signalling molecules that are intricately involved in the control of the immune response and are therefore good positional candidates.

Background: Mode of inheritance of equine recurrent airway obstruction (RAO) is unknown. Hypothesis: Major genes are responsible for RAO. Animals: Direct offspring of 2 RAO-affected Warmblood stallions (n 5 197; n 5 163) and a representative sample of Swiss Warmbloods (n 5 401).Methods: One environmental and 4 genetic models (general, mixed inheritance, major gene, and polygene) were tested for Horse Owner Assessed Respiratory Signs Index (1-4, unaffected to severely affected) by segregation analyses of the 2 half-sib sire families, both combined and separately, using prevalences estimated in a representative sample.Results: In all data sets the mixed inheritance model was most likely to explain the pattern of inheritance. In all 3 datasets the mixed inheritance model did not differ significantly from the general model (P 5 .62, P 5 1.00, and P 5 .27) but was always better than the major gene model (P o .01) and the polygene model (P o .01). The frequency of the deleterious allele differed considerably between the 2 sire families (P 5 .23 and P 5 .06). In both sire families the displacement was large (t 5 17.52 and t 5 12.24) and the heritability extremely large (h 2 5 1). Conclusions and Clinical Relevance: Segregation analyses clearly reveal the presence of a major gene playing a role in RAO. In 1 family, the mode of inheritance was autosomal dominant, whereas in the other family it was autosomal recessive. Although the expression of RAO is influenced by exposure to hay, these findings suggest a strong, complex genetic background for RAO.

Nonalcoholic fatty liver disease (NAFLD) emerges as an important global burden and Helicobacter pylori infection (Hp-I) has been suggested as a risk factor of NAFLD, although controversy exists. This retrospective study aimed to investigate a potential impact of active Hp-I on NAFLD severity in morbidly obese patients, subjected to bariatric surgery and gastric biopsy for documentation of Hp-I. Of 64 eligible participants, 15 (23.4%) were diagnosed with active Hp-I, showing higher rates of nonalcoholic steatohepatitis (NASH) than those without Hp-I (86.7% vs. 26.5%, respectively; p < 0.001). Concerning histological lesions, steatosis grade (p = 0.027), ballooning (p < 0.001), lobular inflammation (p = 0.003), and fibrosis stage (p < 0.001) were also more severe in Hp-I positive patients. Likewise, liver function tests, insulin resistance, dyslipidemia, and arterial hypertension were significantly higher in Hp-I positive patients. Hp-I was independently positively associated with NASH (beta = 3.27; p = 0.002), severe NASH (beta = 2.37; p = 0.018), and the presence of fibrosis (beta = 3.86; p = 0.001) in a binary regression model, after adjustment for potential confounders. In conclusion, active Hp-Ι was independently associated with NASH and fibrosis, findings offering potential clinical implication.

Identification of major genes for RAO may provide a basis for breeding and individual prevention for this important disease.

Recurrent airway obstruction (RAO) is a common and potentially debilitating lower airway disease in horses, which shares many similarities with human asthma. In susceptible horses RAO exacerbation is caused by environmental allergens and irritants present in hay dust. The objective of this study was the identification of genes and pathways involved in the pathology of RAO by global transcriptome analyses in stimulated peripheral blood mononuclear cells (PBMCs). We performed RNA-seq on PBMCs derived from 40 RAO affected and 45 control horses belonging to three cohorts of Warmblood horses: two half-sib families and one group of unrelated horses. PBMCs were stimulated with hay dust extract, lipopolysaccharides, a recombinant parasite antigen, or left unstimulated. The total dataset consisted of 561 individual samples. We detected significant differences in the expression profiles between RAO and control horses. Differential expression (DE) was most marked upon stimulation with hay dust extract. An important novel finding was a strong upregulation of CXCL13 together with many genes involved in cell cycle regulation in stimulated samples from RAO affected horses, in addition to changes in the expression of several HIF-1 transcription factor target genes. The RAO condition alters systemic changes observed as differential expression profiles of PBMCs. Those changes also depended on the cohort and stimulation of the samples and were dominated by genes involved in immune cell trafficking, development, and cell cycle regulation. Our findings indicate an important role of CXCL13, likely macrophage or Th17 derived, and the cell cycle regulator CDC20 in the immune response in RAO.

Complete transcriptomic data at high resolution are available only for a few model organisms with medical importance. The gene structures of non-model organisms are mostly computationally predicted based on comparative genomics with other species. As a result, more than half of the horse gene models are known only by projection. Experimental data supporting these gene models are scarce. Moreover, most of the annotated equine genes are single-transcript genes. Utilizing RNA sequencing (RNA-seq) the experimental validation of predicted transcriptomes has become accessible at reasonable costs. To improve the horse genome annotation we performed RNA-seq on 561 samples of peripheral blood mononuclear cells (PBMCs) derived from 85 Warmblood horses. The mapped sequencing reads were used to build a new transcriptome assembly. The new assembly revealed many alternative isoforms associated to known genes or to those predicted by the Ensembl and/or Gnomon pipelines. We also identified 7,531 transcripts not associated with any horse gene annotated in public databases. Of these, 3,280 transcripts did not have a homologous match to any sequence deposited in the NCBI EST database suggesting horse specificity. The unknown transcripts were categorized as coding and noncoding based on predicted coding potential scores. Among them 230 transcripts had high coding potential score, at least 2 exons, and an open reading frame of at least 300 nt. We experimentally validated 9 new equine coding transcripts using RT-PCR and Sanger sequencing. Our results provide valuable detailed information on many transcripts yet to be annotated in the horse genome.

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