Unraveling the genetic cause of patent ductus arteriosus in the Friesian Stabyhoun.

Abstract

Patent ductus arteriosus is one of the most common congenital heart diseases in the dog. During fetal growth, the ductus arteriosus allows blood to flow from the pulmonary artery into the aorta so that the not-functioning lungs are bypassed. The two main factors that keep the ductus open are the low oxygen tension in the blood and the high levels of prostaglandin E2 from the placenta. Within minutes to hours after birth, the vessel constricts and closes due to a rise in oxygen tension and the deterioration of placental PGE2. In case of PDA, the ductus arteriosus fails to close after birth. In dogs with PDA, a very typical continuous murmur can be heard on the left heart base. Untreated, PDA will cause death within the first year in one third of all cases. Histopathological, asymmetry and hypoplasia of the ductus muscle is seen. Also, parts of the ductus muscle contain non-contracting aorta like elastic structure. Several dog breeds are predisposed, indicating that there is a genetic component in the disease. However, in dogs, no causative gene mutations associated with the occurrence of PDA are described yet. The Friesian Stabyhoun, a Dutch breed with a small genetic base, seems to have an increased risk of PDA. Pedigree analysis revealed a high prevalence (0,55%) and inheritance (0.4). In previous association and sequence studies, 157 possible causal single nucleotide polymorphisms within two small chromosomal regions were found. The objective of this study is to make a start in elucidating gene mutations that are possibly involved in the development of PDA in the Friesian Stabyhoun. In this research, the top 18 SNPs with the lowest p-values were screened in a group of Stabyhouns as well as a group of other breeds, using KASPTM genotyping. In the group of Stabyhoun samples (21 cases and 171 controls), a significant difference between cases and controls in allele frequency was found for two SNPs on chromosome 5. One of these SNPs is located on the PDA1 gene, which is expressed in vascular smooth muscle cells and plays a role in contractility of vascular smooth muscles. A mutation in this gene may lead to an impaired development and contractility of vascular smooth muscle cells. The second SNP is located on the PDA2 gene, a gene that is involved in maintaining the growth and absorptive function of the intestinal villi. In the group of other breeds (77 cases and 73 controls), significances were found for one SNP in allele frequency and for one SNP in genotype frequency, but they were not conclusive. Results of this study show possible involvement of two mutations in the development of PDA in the Friesian Stabyhoun. However, PDA is a complex polygenic disease and further research is needed to find out the exact mechanism of the genetic cause of this disease. Only then, a genetic test can be developed and patients and carriers can be excluded from breeding. Additionally, the Stabyhoun dog might be a good model for other dog breeds and human, because of the small genetic base and the high prevalence of the disease in this breed.