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

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.

Genome-wide association study of degenerative mitral valve disease in Maltese dogs

“…Thus, the genetic transmission of DMVD could be revealed through precision mapping of concentrated markers in susceptible breeds. Recently, one study identified DMVD-associated loci in Whippets dogs, which is a large dog breed with a tendency to exhibit DMVD [31]. In the present study, Maltese dogs were evaluated because they are the most common breed that presents at animal hospitals in Korea.…”

Disease Severity-Associated Gene Expression in Canine Myxomatous Mitral Valve Disease Is Dominated by TGFβ Signaling

“…The disease in the dog is characterized by its ubiquity, such that all dogs will eventually develop some evidence of the disease, and there is a close relationship between age and disease severity (Han et al, 2010(Han et al, , 2013. Several pedigree breeds have a heightened susceptibility to develop the disease sooner, progress more rapidly and become more severely affected (Beardow and Buchanan, 1993;Stern et al, 2015;Lu et al, 2016). While familial valvulopathies are also found in human patients, nonsyndromic BD seems to show the closest parallels with canine MMVD as it becomes apparent between the fourth and sixth decade, but the exact prevalence in the younger adult population is unknown (Levine et al, 2015;Markby G. R. et al, 2017;Gasser et al, 2018).…”

A Genomic Study of Myxomatous Mitral Valve Disease in Cavalier King Charles Spaniels

“…In 2015, Stern et al tried to solve this problem by associating their results with the whippet dog breed with a continuous variable that included the age of onset of the MMVD (considered early if under 5 years of age) and a score of severity. In this study, a genome-wide significant association was identified on the region of CFA 15, containing FSTL5, and of CFA 2, containing ARHGAP26 [ 21 ].…”