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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.

Background: Reliability of echocardiographic measurements of left atrial (LA) size, an important marker of disease severity, has not been reported in dogs with myxomatous mitral valve disease (MMVD). Objectives: To define and compare reliability of left atrial dimension/diameter (LAD), LAD indexed to aortic valve diameter (LAD/AoD), left atrium-to-aortic root ratio (LA/Ao), left atrial volume acquired from a right parasternal long-axis (LAV RPLx), and left apical view (LAV LAP) in dogs with subclinical MMVD. Animals: Nine dogs with subclinical MMVD. Methods: Prospective reproducibility study. Dogs underwent 12 echocardiographic examinations by 2 operators on the mornings and afternoons of 3 nonconsecutive days within 1 week. Reliability (measurement variability) was quantified using coefficients of variation (CV) and 95% repeatability/reproducibility coefficients (95% RC). A mixed-model analysis of variance (ANOVA) was used to determine if time of day, day, and operator were significant sources of variability for each index. Results: Linear measurements (LAD, LAD/AoD, and LA/Ao) exhibited less within-day, between-day, and interoperator variability (CVs, 3.9%-12.5%) than did volume estimate measurements (LAV RPLx and LAV LAP ; CVs, 11.8%-17.9%). Of the linear measurements, LA/Ao exhibited greater variability (CVs, 9.9%-12.5%) compared to LAD and LAD/AoD (CVs, 3.9%-4.9%). Operator was a significant (P = .005) source of variability for LA/Ao. Conclusions and Clinical Importance: Compared to other linear measurements, LA/Ao was the least reproducible and most dependent on operator. The 95% RC for each LA size index are provided to help identify clinically relevant changes (beyond intraoperator or interoperator variability) during serial echocardiographic examinations of dogs with subclinical MMVD.

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