Severity of Mitral Valve Degeneration Is Associated with Chromosome 15 Loci in Whippet Dogs.
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.
University of California Davis, Department of Medicine & Epidemiology, One Shields Ave, Davis, California, 95616, United States of America.
Joshua A
JA
Stern
University of California Davis, Department of Medicine & Epidemiology, One Shields Ave, Davis, California, 95616, United States of America.
Weihow
W
Hsue
University of California Davis, Department of Medicine & Epidemiology, One Shields Ave, Davis, California, 95616, United States of America.
Kun-Ho
KH
Song
University of California Davis, Department of Medicine & Epidemiology, One Shields Ave, Davis, California, 95616, United States of America.
Eric S
ES
Ontiveros
Clinical Science and Services, Royal Veterinary College, Hawkshead Lane, North Mymms, Hertfordshire, AL9 7TA, United Kingdom.
Virginia
V
Luis Fuentes
University of Wisconsin, School of Veterinary Medicine, Department of Medical Sciences (Cardiology), 2015 Linden Drive, Madison, Wisconsin, 53706, United States of America.
Rebecca L
RL
Stepien
D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics*; D004283:Dog Diseases / Q000235:genetics* / Q000473:pathology*; D004285:Dogs; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D008297:Male; D008943:Mitral Valve / Q000473:pathology; D008944:Mitral Valve Insufficiency / Q000235:genetics* / Q000473:pathology*