Replication and fine‐mapping of a QTL for recurrent airway obstruction in European Warmblood horses

Abstract

Recurrent airway obstruction (RAO), or 'heaves', is a common performance-limiting allergic respiratory disease of mature horses. It is related to sensitization and exposure to mouldy hay and has a familial basis with a complex mode of inheritance. In a previous study, we detected a QTL for RAO on ECA 13 in a half-sib family of European Warmblood horses. In this study, we genotyped additional markers in the family and narrowed the QTL down to about 1.5 Mb (23.7-25.2 Mb). We detected the strongest association with SNP BIEC2-224511 (24,309,405 bp). We also obtained SNP genotypes in an independent cohort of 646 unrelated Warmblood horses. There was no genome-wide significant association with RAO in these unrelated horses. However, we performed a genotypic association study of the SNPs on ECA 13 in these unrelated horses, and the SNP BIEC2-224511 also showed the strongest association with RAO in the unrelated horses (p(raw) = 0.00037). The T allele at this SNP was associated with RAO both in the family and the unrelated horses. Thus, the association study in the unrelated animals provides independent support for the previously detected QTL. The association study allows further narrowing of the QTL interval to about 0.5 Mb (24.0-24.5 Mb). We sequenced the coding regions of the genes in the critical region but did not find any associated coding variants. Therefore, the causative variant underlying this QTL is likely to be a regulatory mutation.

Multiple Hypersensitivities Including Recurrent Airway Obstruction, Insect Bite Hypersensitivity, and Urticaria in 2 Warmblood Horse Populations

“…The SNP BIEC2‐224511 on ECA 13 near the IL4RA gene previously has been found to be associated with RAO both in a high‐prevalence family and in unrelated horses 16. As expected, because our P2 was a subset of the latter unrelated horses, cross tabulation confirmed these earlier results.…”

“…P2 represents a subset of a previously investigated population 16. Horses were selected based on age and breed (as defined above), and excluded if there was incomplete information or first degree parental relationships.…”

“…Genetic linkage between equine RAO and a region on equine chromosome (ECA) 13 containing the gene for IL4RA was described in a high‐prevalence RAO family 15. An association of RAO with a single nucleotide polymorphism (SNP BIEC2‐224511 ) on ECA 13 near IL4RA recently was confirmed in unrelated cases and controls 16. Moreover, RAO has been shown to be associated with increased resistance against strongylid nematodes,17, 18 which is in agreement with the hygiene hypothesis first proposed by Strachnan 19.…”

Identification of key contributors in complex population structures

“…The population structure of this breed is based upon the formation of 11 major stallion lineages, where especially three of these lineages show a high level of admixture with Arabian and Warmblood horses, respectively. In order to determine the level of admixture of crossbred FM horses, we additionally included the SNP genotype information of 600 Warmblood horses [44] in the data. Post QC (MAF >0.05, call rate >0.9 and Hardy Weinberg Equilibrium (HWE) P >0.0001) we included 38,124 SNP genotypes of the FM horses for the final analyses.…”

RAO – invasive and non invasive methods

“…Beim Rennen steigt der Bedarf auf bis zu 1.800 L/min (Art et al 1990, Art und Leceux 1993 (Gerber et al 2003). Auch wird eine erhöhte intra-pleurale Druckdifferenz zwischen Ein-und Ausatmung (dPPl max ) (Deegen und Klein 1987) (Gerber et al 2009, Klukowska-Rötzler et al 2012, Shakhsi-Niaei et al 2012 (Pirie et al 2003, Deaton et al 2007, Ghio et al 2006. Bis jetzt konnte jedoch noch nicht nachgewiesen werden, dass ein längerfristiger Aufenthalt in herkömmlichen Stallungen die IAD-Symptome verschlimmerte (Gerber et al, 2003 Charakteristisch für eine Atemwegserkrankung ist eine stärke-re Frequenzabhängigkeit der Impedanz bei lungenkranken Pferden (höhere Impedanz bei tiefen Frequenzen).…”