Severity of Mitral Valve Degeneration Is Associated with Chromosome 15 Loci in Whippet Dogs.

Joshua A Stern,Eric S Ontiveros,Rebecca L Stepien,Weihow Hsue,Kun-Ho Song,Virginia Luis Fuentes

doi:10.1371/journal.pone.0141234

Abstract

Mitral valve degeneration (MVD) is the most common form of heart disease in dogs, frequently leading to left-sided congestive heart failure and cardiac mortality. Although breed-specific disease characteristics and overrepresentation point towards a genetic origin for MVD, a causative mutation and complete molecular pathogenesis are unknown. Whippet dogs are overrepresented in incidence of MVD, suggesting an inherited component in this breed. Expressivity of this condition is variable with some dogs showing evidence of more severe disease at earlier ages than other dogs. This phenomenon makes a traditional case versus control genetic study prone to phenotyping error. This study sought to avoid these common pitfalls by identifying genetic loci associated with severity of MVD in Whippets through a genome-wide association study (GWAS). 138 Whippet dogs were characterized for MVD by echocardiographic examination and a novel disease severity score was developed and adjusted for age in each subject. Single nucleotide polymorphism (SNP) genotype data (170k Illumina CanineHD SnpChip) was obtained for DNA isolated from blood of each study subject. Continuous variable genome wide association was performed after correction for population stratification by efficient mixed model association expedited (EMMAX) in 130 dogs. A genome wide significant association was identified on chromosome 15 (peak locus 57,770,326; Padj = 0.049) and secondary loci of suggestive association were identified on chromosome 2 (peak locus 37,628,875; Padj = 0.079). Positional candidate genes were identified within the primary and secondary loci including follistatin-related protein 5 precursor (FSTL5) and Rho GTPase-activating protein 26 (ARHGAP26). These results support the hypothesis that severity of MVD in whippets has a genetic basis and warrants further study by either candidate gene sequencing or next-generation techniques.

Highlights

Mitral valve degeneration (MVD) is the most common form of heart disease in dogs, accounting for 75% of all dogs with cardiac disease [1]. The pathology of this disease in the dog resembles that of primary mitral valve prolapse (MVP) of humans in some respects [2]
This score was derived based upon the noted presence or severity of pre-determined echocardiographic findings as noted by the reporting cardiologist including: mitral valve prolapse, mild mitral valve regurgitation (MR), and chamber enlargement
The age-related penetrance of MVD makes identification of true control dogs difficult as it is impossible to determine if a Echocardiographic Variable Mitral Valve Prolapse Mitral Valve Regurgitation

Summary

Introduction

Mitral valve degeneration (MVD) is the most common form of heart disease in dogs, accounting for 75% of all dogs with cardiac disease [1] The pathology of this disease in the dog resembles that of primary mitral valve prolapse (MVP) of humans in some respects [2]. The disease is characterized by chronic progressive degenerative lesions of the mitral valve, where the valve leaflets become thickened, develop poor coaptation, and may prolapse during systole into the left atrium [6]. These valve lesions result in mitral regurgitation, elevated left atrial pressure and, in some dogs, left-sided congestive heart failure and cardiac mortality [7]

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