Faculty of Science, School of Life and Environmental Sciences Camperdown, The University of Sydney, Sydney, NSW 2006, Australia.
Veterinaire Specialisten Vught, Reutsedijk 8a, 5264 Vught, The Netherlands.
Genes (Basel). 2022 Dec 5;13(12):2292. doi: 10.3390/genes13122292.
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 () 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 , and 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 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 exist in low frequency in the CKCS breed and can be used to reduce MMVD severity and mortality.
在宠物犬中最常见的心血管疾病是黏液样心肌二尖瓣病（MMVD），占所有心脏病的 75%。一般来说，年龄的增长与疾病发病率的增加有关，但查理士王小猎犬（CKCS）表现出异常高的早发性 MMVD 发病率，因此与其他品种相比，可能有更大的心脏发病率和死亡率。以前的研究表明，MMVD 的一些候选风险等位基因在 CKCS 中是固定的，包括 CFA2 上的基因中的六个位置。本研究分析了 180 只澳大利亚 CKCS 在已确定的风险基因座的基因型。其中，178 只通过超声心动图测量左心房与主动脉根比值（LA:Ao）和左心室舒张末期直径（LVIDdN）标准化体重来对疾病严重程度进行表型分析。基因分型阵列标记物正确预测了 CKCS 群体中风险变体基因座的基因型，并且在该队列中观察到、和变体处于完美的连锁不平衡状态。CKCS 队列包括 6/178 只狗在 NEBL 基因座的保护性/野生型等位基因中是杂合的。在变体中杂合的这些狗的平均 LA:Ao 和 LVIDdN 评分明显较小，与风险等位基因纯合的年龄匹配的 CKCS 相比，方差明显更低。杂合狗的较低心脏测量值表明其患有严重 MMVD 疾病的风险显著降低。我们的分析表明，尽管 NEBL 风险等位基因相对固定，但 CKCS 品种中存在低频率的健康参考等位基因，可用于降低 MMVD 严重程度和死亡率。
