WP2 Cardiovascular disorders

WP2.1 Dilated cardiomyopathy (DCM) – Leader : Antagene

Idiopathic dilated cardiomyopathy has a prevalence of about 36.5 per 100,000 in humans. It accounts for more than 10,000 deaths in the U.S. annually and is the primary indication for cardiac transplantation. Familial occurrence accounts for 20 to 25% of cases. Mutations in several genes have been found to cause different forms of DCM, yet many DCM families remain “orphan”. Identifying DCM genes in the dog may contribute in the identification of novel susceptibility genes, and provide well characterized model systems for further studies into pathogenesis and therapy.

DCM is a common cause of congestive heart failure and sudden death in the dog. It is a well defined clinical entity that is diagnosed using standardized criteria by means of ECG, echocardiography and/or tissue Doppler imaging, and – when possible – post-mortem examination. It is particularly common in Newfoundland, Doberman, Irish wolfhound and Great Danes. Increased prevalence in specific breeds combined with familial clustering within breeds supports an inherited component. Segregation analysis supports an autosomal dominant mode of inheritance in Doberman. Our goal is the identification of genetic factors responsible for DCM in these different dog breeds.

WP2.2 Myxomatous mitral valve disease (MMVD) – Leader : University of Copenhagen

Primary mitral valve prolapse (MVP also called Barlows disease) is a common disorder in human characterized by systolic displacement or billowing of the mitral leaflets into the left atrium, often accompanied by mitral regurgitation. It has many characteristics similar to MMVD in dogs. MVP is genetically heterogeneous and is inherited as an autosomal dominant trait that exhibits both sex- and age-dependent penetrance. Several loci for mitral valve prolapse (MVP) have been mapped: MMVP1 to chromosome 16p; MMVP2 to chromosome 11p, and MMVP3 to chromosome 13q but due to the limited number of informative individuals/families available no causal genes and mutations have been identified for the corresponding loci. Recently, mutations in filamin A were incriminated in X-linked cases.

MMVD is the most common heart disease in dogs. The disease is also known as endocardiosis or chronic valvular disease. It typically evolves in three stages: (i) mitral valve prolapse or thickening of the valve without regurgitation, (ii) mitral regurgitation in the absence of other signs of heart failure, (iii) heart failure. It is easily diagnosed using auscultation and echocardiography. MMVD is characterized by a clear breed predisposition, most often in small to medium size breeds. Nearly 100% of Cavalier King Charles Spaniels (CKCS) suffer from the condition at 10 years of age, while approximately 50% Dachshund have MMVD at the same age. The aim of this study is the identification of genetic factors responsible for the development of MMVD in dogs.

WP2.3 Identification of genetic determinants of variation in blood pressure, glucose and lipid metabolism in healthy dogs – Leader : University of Liège

The objective of this project is to provide an alternative way towards the identification of genes that influence blood pressure, glucose and lipid metabolism, i.e. the major physiological determinants of hypertension and metabolic syndrome. These disorder are the main cause of death in Europe, counting for nearly half (49%) of all mortalities and costing the EU economy €169 billion a year. Rather than to focus on diseased dogs suffering from pathologies resembling metabolic syndrome and essential hypertension in human, we have elected to study the molecular basis of the physiological variation observed amongst healthy dogs. Indeed, this approach will allow us to collect samples that have been rigorously standardized for a series of environmental factors that would cause considerable noise in other experimental designs. Identifying genes underlying the physiological variation for blood pressure, glucose and lipid metabolism in the dog is bound to lead to groundbreaking insights in physiological mechanisms, novel targets for drug design and candidate genes for human association studies.