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 Patrick T Ellinor |
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Science
Genetics of Atrial Fibrillation
Atrial fibrillation (AF) is the most common significant cardiac arrhythmia affecting over 2 million Americans. It leads to an increased risk of stroke, congestive heart failure and death. Although most AF is associated with other cardiovascular conditions, 10-30% of patients have isolated or lone AF.
Since 2001 we have been enrolling patients with lone AF in a study to learn more about the genetic contribution to this arrhythmia. We have currently enrolled over 600 patients and family members with this condition. Using this cohort we have found:
• A novel locus for familial AF on Chromosome 6.
• Discordant levels of natriuretic peptides in lone AF.
• Reduced levels of apelin, a marker of heart failure, in patients with lone AF.
• Elevated levels of CRP in subjects with AF and hypertension, but not in subjects with
lone AF.
• Potassium channel mutations are a rare cause of familial AF.
In an initial genetic study of lone atrial fibrillation, we have found a high rate of familial aggregation in patients with this arrhythmia. From our study of 120 individuals with lone atrial fibrillation, we have illustrated the pedigrees of those subjects with an affected family member. Click here to see the figure. In this figure, men are indicated by squares, women by circles, affected individuals in black, and unaffected individuals in white. The proband is indicated by the arrowhead. More that 35% of subjects with lone atrial fibrillation reported a family history of this condition.
We welcome families with an extensive history of atrial fibrillation to participate in the study (generally 5 or more people in a family with atrial fibrillation). If you are a patient with any of these conditions and you would like to learn more about this research project please contact our research nurse Marisa Shea by clicking here.
Familial Arrhythmias
A second major goal of the laboratory has been to identify the molecular basis of rare familial arrhythmias including:
• Arrhythmogenic Right Ventricular Dysplasia
• Brugada Syndrome
• Long QT syndrome
• Short QT syndrome
• Exercise induced ventricular tachycardia
As part of a collaborative effort, we have found that mutations in a desmosomal protein, plakophilin-2, are present in over one-quarter of patients with arrhythmogenic right ventricular dysplasia (ARVD). In ongoing efforts, we are examining the role of other desmosomal proteins in subjects with ARVD and exploring the role of these proteins in a zebrafish model system.
We have recently identified a large family with dilated cardiomyopathy, fibrosis and sudden death. We have mapped this family to a novel locus on the long arm of chromosome 10 and are in the process of identifying the specific genetic defect, please click here to view the figure. In this figure, men are indicated by squares, women by circles, affected individuals in black, unaffected individuals in white and unknown individuals are hatched. The genotypes from centromere to telomere are indicated below each individual and the minimal disease interval is indicated by the black line.
If you are a patient with any of these conditions and you would like to learn more about this research project please contact our research nurse Marisa Shea by clicking here.
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Fig 1: Schematic of the known cardiomyopathic pathways.
The four known pathways for human cardiomyopathy are depicted in this diagram. Desmosomal perturbations appear to uniquely affect the right ventricle leading to ARVC. More typical dilated cardiomyopathy is a result of mutations which affect the structural integrity of the cardiomyocyte through perturbations of the dystrophin-associated glycoprotein complex, the cytoskeleton or more rarely the nuclear envelope. Mutations in sarcomeric contractile protein genes usually result in hypertrophic cardiomyopathy, but can cause dilated ventricular phenotypes. From this simplified diagram it can be seen that these protein complexes are directly and indirectly linked to each other.
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Fig 2: The inset depicts the molecular composition of the desmosome. The desmosomal cadherins desmocollin and desmoglein form classic homotypic and heterotypic interactions between cells. These membrane bound proteins are linked through the armadillo-family members, plakoglobin and plakophilin to the intermediate filament binding protein desmoplakin. This complex anchors the desmosome to the cytoskeleton of the cell, and thus indirectly to the sarcomere, nuclear
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| membrane and the dystrophin associated glcyoproteins. |
Collaborative Relationships
Patrick T. Ellinor's lab is part of the Developmental Biology Program and works closely with the labs of Calum A. MacRae and David Milan.
Selected Publications:
To find out more about Patrick T. Ellinor's research please read these selected publications or click here to view all publications.
Atrial fibrillation:
Ellinor, P.T., Shin, J.T., Yoerger, D.M., Moore, R.K., and MacRae, C.M. A Locus for Atrial Fibrillation Maps to Chromosome 6q14-16. Circulation 2003; 23: 2880-3.
Ellinor, P.T., Low, A.M., Patton, K.K., Shea, M.A. and MacRae, C.M. Discordant ANP and BNP Levels in Lone Atrial Fibrillation. JACC 2005, 45(1):82-6.
Ellinor, P.T., Yoerger, D.M., Ruskin, J.N., and MacRae, C.M. Familial Aggregation in Lone Atrial Fibrillation. Human Genetics, 2005 Nov;118(2):179-84.
ARVD:
Gerull, B., Heuser, A., Wichter, T., Paul, M., Basson, C.T., McDermott, B.A., Lerman, B.B., Markowitz, S.M., Ellinor, P.T., MacRae5, C.A., Peters, S., Grossmann, K.S., Michely, B., Sasse-Klaassen, B., Birchmeier, W., Dietz, R., Breithardt, G., Schulze-Bahr, E., and Thierfelder, L. L. Mutations in the desmosomal arm repeat protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nature Genetics 2004; 36(11):1162-4.
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