Genetic Variants at the Nebulette Locus Are Associated with Myxomatous Mitral Valve Disease Severity in Cavalier King Charles Spaniels
The most common cardiovascular disease in domestic dogs is myxomatous mitral valve disease (MMVD), accounting for 75% of all cardiac disease. An increase in age is generally associated with increased incidence of the disease, but Cavalier King Charles Spaniels (CKCS) exhibit an unusually high preval...
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MDPI AG
2022-12-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/13/12/2292 |
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| author | Sophie E. Mead Niek J. Beijerink Mitchell O’Brien Claire M. Wade |
| author_facet | Sophie E. Mead Niek J. Beijerink Mitchell O’Brien Claire M. Wade |
| author_sort | Sophie E. Mead |
| collection | DOAJ |
| description | The most common cardiovascular disease in domestic dogs is myxomatous mitral valve disease (MMVD), accounting for 75% of all cardiac disease. An increase in age is generally associated with increased incidence of the disease, but Cavalier King Charles Spaniels (CKCS) exhibit an unusually high prevalence of early-onset MMVD, and thus, potentially greater cardiac morbidity and mortality compared to other breeds. Previous research has suggested that selected candidate risk alleles for MMVD are fixed in CKCSs, including six locations within the <i>Nebulette</i> (<i>NEBL</i>) gene on CFA2. The current study analysed genotypes of 180 Australian CKCSs at the identified risk loci. Of these, 178 were phenotyped for severity of disease by echocardiographic measurements of left atrium to aortic root ratio (LA:Ao) and weight normalised left ventricular end diastolic diameter (LVIDdN). Genotyping array markers correctly predicted the genotype at the risk-variant loci in the CKCS population, and the <i>NEBL1</i>, <i>NEBL2</i> and <i>NEBL3</i> variants were observed to be in perfect linkage disequilibrium in this cohort. The CKCS cohort included 6/178 dogs being heterozygous for the protective/wild-type alleles at the NEBL locus. The mean LA:Ao and LVIDdN scores of these dogs heterozygous at <i>NEBL1-3</i> variants were significantly smaller, and with significantly lower variance compared to age-matched CKCSs that were homozygous for risk alleles. The lower cardiac measurements in the heterozygous dogs indicate a significantly reduced risk of severe MMVD disease. Our analysis suggests that despite relative fixation of the NEBL risk alleles, healthy reference alleles at <i>NEBL1-3</i> exist in low frequency in the CKCS breed and can be used to reduce MMVD severity and mortality. |
| first_indexed | 2024-03-09T16:29:19Z |
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| last_indexed | 2024-03-09T16:29:19Z |
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| spelling | doaj.art-4dfeb6dcbf1441a7b257ae2f6df54fde2023-11-24T15:04:25ZengMDPI AGGenes2073-44252022-12-011312229210.3390/genes13122292Genetic Variants at the Nebulette Locus Are Associated with Myxomatous Mitral Valve Disease Severity in Cavalier King Charles SpanielsSophie E. Mead0Niek J. Beijerink1Mitchell O’Brien2Claire M. Wade3Faculty of Science, School of Life and Environmental Sciences Camperdown, The University of Sydney, Sydney, NSW 2006, AustraliaFaculty of Science, School of Life and Environmental Sciences Camperdown, The University of Sydney, Sydney, NSW 2006, AustraliaTransformational Bioinformatics, Health and Biosecurity, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Westmead, NSW 2145, AustraliaFaculty of Science, School of Life and Environmental Sciences Camperdown, The University of Sydney, Sydney, NSW 2006, AustraliaThe most common cardiovascular disease in domestic dogs is myxomatous mitral valve disease (MMVD), accounting for 75% of all cardiac disease. An increase in age is generally associated with increased incidence of the disease, but Cavalier King Charles Spaniels (CKCS) exhibit an unusually high prevalence of early-onset MMVD, and thus, potentially greater cardiac morbidity and mortality compared to other breeds. Previous research has suggested that selected candidate risk alleles for MMVD are fixed in CKCSs, including six locations within the <i>Nebulette</i> (<i>NEBL</i>) gene on CFA2. The current study analysed genotypes of 180 Australian CKCSs at the identified risk loci. Of these, 178 were phenotyped for severity of disease by echocardiographic measurements of left atrium to aortic root ratio (LA:Ao) and weight normalised left ventricular end diastolic diameter (LVIDdN). Genotyping array markers correctly predicted the genotype at the risk-variant loci in the CKCS population, and the <i>NEBL1</i>, <i>NEBL2</i> and <i>NEBL3</i> variants were observed to be in perfect linkage disequilibrium in this cohort. The CKCS cohort included 6/178 dogs being heterozygous for the protective/wild-type alleles at the NEBL locus. The mean LA:Ao and LVIDdN scores of these dogs heterozygous at <i>NEBL1-3</i> variants were significantly smaller, and with significantly lower variance compared to age-matched CKCSs that were homozygous for risk alleles. The lower cardiac measurements in the heterozygous dogs indicate a significantly reduced risk of severe MMVD disease. Our analysis suggests that despite relative fixation of the NEBL risk alleles, healthy reference alleles at <i>NEBL1-3</i> exist in low frequency in the CKCS breed and can be used to reduce MMVD severity and mortality.https://www.mdpi.com/2073-4425/13/12/2292congestive heart failuredoggeneticsheart diseasemyxomatous mitral valve diseasenebulette |
| spellingShingle | Sophie E. Mead Niek J. Beijerink Mitchell O’Brien Claire M. Wade Genetic Variants at the Nebulette Locus Are Associated with Myxomatous Mitral Valve Disease Severity in Cavalier King Charles Spaniels Genes congestive heart failure dog genetics heart disease myxomatous mitral valve disease nebulette |
| title | Genetic Variants at the Nebulette Locus Are Associated with Myxomatous Mitral Valve Disease Severity in Cavalier King Charles Spaniels |
| title_full | Genetic Variants at the Nebulette Locus Are Associated with Myxomatous Mitral Valve Disease Severity in Cavalier King Charles Spaniels |
| title_fullStr | Genetic Variants at the Nebulette Locus Are Associated with Myxomatous Mitral Valve Disease Severity in Cavalier King Charles Spaniels |
| title_full_unstemmed | Genetic Variants at the Nebulette Locus Are Associated with Myxomatous Mitral Valve Disease Severity in Cavalier King Charles Spaniels |
| title_short | Genetic Variants at the Nebulette Locus Are Associated with Myxomatous Mitral Valve Disease Severity in Cavalier King Charles Spaniels |
| title_sort | genetic variants at the nebulette locus are associated with myxomatous mitral valve disease severity in cavalier king charles spaniels |
| topic | congestive heart failure dog genetics heart disease myxomatous mitral valve disease nebulette |
| url | https://www.mdpi.com/2073-4425/13/12/2292 |
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