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BMC genomics2018; 19(1); 581; doi: 10.1186/s12864-018-4938-9

eQTL discovery and their association with severe equine asthma in European Warmblood horses.

Abstract: Severe equine asthma, also known as recurrent airway obstruction (RAO), is a debilitating, performance limiting, obstructive respiratory condition in horses that is phenotypically similar to human asthma. Past genome wide association studies (GWAS) have not discovered coding variants associated with RAO, leading to the hypothesis that causative variant(s) underlying the signals are likely non-coding, regulatory variant(s). Regions of the genome containing variants that influence the number of expressed RNA molecules are expression quantitative trait loci (eQTLs). Variation associated with RAO that also regulates a gene's expression in a disease relevant tissue could help identify candidate genes that influence RAO if that gene's expression is also associated with RAO disease status. Results: We searched for eQTLs by analyzing peripheral blood mononuclear cells (PBMCs) from two half-sib families and one unrelated cohort of 82 European Warmblood horses that were previously treated in vitro with: no stimulation (MCK), lipopolysaccharides (LPS), recombinant cyathostomin antigen (RCA), and hay-dust extract (HDE). We identified high confidence eQTLs that did not violate linear modeling assumptions and were not significant due to single outlier individuals. We identified a mean of 4347 high confidence eQTLs in four treatments of PBMCs, and discovered two trans regulatory hotspots regulating genes involved in related biological pathways. We corroborated previous RAO associated single nucleotide polymorphisms (SNPs), and increased the resolution of past GWAS by analyzing 1,056,195 SNPs in 361 individuals. We identified four RAO-associated SNPs that only regulate gene expression of dexamethasone-induced protein (DEXI), however we found no significant association between DEXI gene expression and presence of RAO. Conclusions: Thousands of genetic variants regulate gene expression in PBMCs of European Warmblood horses in cis and trans. Most high confidence eSNPs are significantly enriched near the transcription start sites of their target genes. Two trans regulatory hotspots on chromosome 11 and 13 regulate many genes involved in transmembrane cell signaling and neurological development respectively when PBMCs are treated with HDE. None of the top fifteen RAO associated SNPs strongly influence disease status through gene expression regulation.
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Publication Date: 2018-08-02 PubMed ID: 30071827PubMed Central: PMC6090848DOI: 10.1186/s12864-018-4938-9Google 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 is an attempt to better understand severe equine asthma, a respiratory condition in horses that significantly affects their performance. By analyzing the genetic variants which regulate gene expression in the blood cells of European Warmblood horses, the researchers discovered thousands of these regulatory variants and increased the resolution of previous genomic studies.

Expression Quantitative Trait Loci (eQTLs)

  • In the study, the team focused on eQTLs, genomic regions containing variations that influence the number of expressed RNA molecules.
  • These eQTLs were believed to provide insights into the underlying genetic variants associated with severe equine asthma, which was hypothesized to involve non-coding, regulatory variants.

Peripheral Blood Mononuclear Cells (PBMCs)

  • The research team analyzed PBMCs (a type of immune cell) from 82 European Warmblood horses, belonging to two familial groups and one unrelated group.
  • The PMBCs were treated in various ways: no stimulation (MCK), with lipopolysaccharides (LPS), recombinant cyathostomin antigen (RCA), and hay-dust extract (HDE), and assessed for any resultant eQTLs.

Findings

  • As a result of this approach, an average of 4347 high-confidence eQTLs was identified from the different treatment methods.
  • Trans regulatory hotspots (regions that regulate numerous genes) were found, notably involved in cell signaling and neurological development when PBMCs were treated with HDE.
  • The study supported previous findings regarding RAO-associated single nucleotide polymorphisms (SNPs), which are variation in a single nucleotide that occurs at a specific position in the genome.
  • This investigation analyzed a vast number of SNPs (1,056,195) in 361 individuals, significantly expanding the scale and resolution of previous genome-wide association studies.

Association with Asthma

  • The study identified four SNPs associated with RAO that regulate the gene expression of dexamethasone-induced protein (DEXI).
  • However, no significant association between DEXI gene expression and the presence of RAO was found.
  • Consequently, none of the top fifteen RAO-associated SNPs had a strong influence on disease status via gene expression regulation.

Conclusions

  • Overall, the study highlights the complexity of the genetic underpinnings of RAO in horses.
  • It shows how vast numbers of genetic variants can regulate gene expressions in PBMCs.
  • However, a direct linkage between these gene expression regulations and the disease status of severe equine asthma was not established in this study, indicating the need for further research in this area.

Cite This Article

APA
Mason VC, Schaefer RJ, McCue ME, Leeb T, Gerber V. (2018). eQTL discovery and their association with severe equine asthma in European Warmblood horses. BMC Genomics, 19(1), 581. https://doi.org/10.1186/s12864-018-4938-9

Publication

BMC genomics
ISSN: 1471-2164
NlmUniqueID: 100965258
Country: England
Language: English
Volume: 19
Issue: 1
Pages: 581
PII: 581

Researcher Affiliations

Mason, Victor C
  • Department of Clinical Veterinary Medicine, Swiss Institute of Equine Medicine, Vetsuisse Faculty, University of Bern, and Agroscope, Länggassstrasse 124, 3012, Bern, Switzerland. victor.mason@vetsuisse.unibe.ch.
Schaefer, Robert J
  • Department of Veterinary Population Medicine, University of Minnesota, 1365 Gortner Ave, Saint Paul, MN, 55108, USA.
McCue, Molly E
  • Department of Veterinary Population Medicine, University of Minnesota, 1365 Gortner Ave, Saint Paul, MN, 55108, USA.
Leeb, Tosso
  • Department of Clinical Research and Veterinary Public Health, Institute of Genetics, Vetsuisse Faculty, University of Bern, Bremgartenstrasse 109A, 3012, Bern, Switzerland.
Gerber, Vinzenz
  • Department of Clinical Veterinary Medicine, Swiss Institute of Equine Medicine, Vetsuisse Faculty, University of Bern, and Agroscope, Länggassstrasse 124, 3012, Bern, Switzerland.

MeSH Terms

  • Animals
  • Asthma / chemically induced
  • Asthma / genetics
  • Asthma / veterinary
  • Dust
  • Gene Expression Profiling / veterinary
  • Gene Expression Regulation
  • Gene Regulatory Networks / drug effects
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study / veterinary
  • Horse Diseases / chemically induced
  • Horse Diseases / genetics
  • Horses
  • Leukocytes, Mononuclear / drug effects
  • Lipopolysaccharides / adverse effects
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci

Grant Funding

  • 31003A-162548/1 / Schweizerischer Nationalfonds zur Fu00f6rderung der Wissenschaftlichen Forschung

Conflict of Interest Statement

All animal experiments were performed according to the local regulations and with the consent of the horse owners. This study was approved by the Animal Experimentation Committee of the Canton of Bern, Switzerland (BE33/07, BE58/10 and BE10/13). Not applicable. The authors declare that they have no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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