Genetics of Atrial Fibrillation and Atrial Cardiomyopathy
Julie H. Andersen1,2*, Morten S. Olesen1,2
1Laboratory for Molecular Cardiology, Centre for Cardiac, Vascular, Pulmonary and Infectious Diseases, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
2Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. Through epidemiological studies, AF has been recognized to have a considerable genetic component. Genome-wide association studies have associated more than 100 genes with AF. Newer research has established a link between atrial cardiomyopathy and a predisposition for AF. This association has been further supported by recent exome and genome sequencing projects which have shown a substantial genetic overlap between genetic variants implicated in AF and cardiomyopathy in general. This review focuses on the genetic overlap between AF and cardiomyopathy.
Atrial fibrillation (AF) affects more than 33 million people worldwide1. It has been linked to a substantial increased morbidity and mortality with a high risk of stroke, heart failure and sudden death1,2. It is well known that AF typically arises secondary to hypertension, ischemic and/or structural heart disease. A number of studies have demonstrated, that AF and in particular lone AF has a substantial genetic component3,4. An Icelandic study demonstrated large familial aggregation of AF in 5,000 Icelandic AF patients4. It has recently been recognized that atrial myopathy and fibrosis appear to play a driving role in the development of AF5. Most AF associated rare genetic variants were initially identified in genes encoding ion channels, particularly potassium and sodium channels6,7,8. These rare variants were shown to have gain-of-function or loss-of-function effects contributing to an altered cardiac depolarization or repolarization8. Mutations in non-ion channel genes were subsequently identified9,10. Rare variants in both ion channel and non-ion channel genes were found to be associated with AF using the candidate gene approach11. During the last decades, more than 100 single-nucleotide polymorphisms have been shown to contribute to the risk of AF through genome-wide association studies12.
Recent discoveries suggest that AF could be caused by atrial cardiomyopathy13. Although cardiomyopathy involve a variety of phenotypes and etiologies, the most common cardiomyopathies are hypertrophic, dilated and restrictive cardiomyopathies, where the latter is less common and mostly associated with systemic disease14.
Overall, Atrial cardiomyopathy has been defined to encompass any complex of structural, architectural, contractile or electrophysiological changes affecting the atria with the potential to produce clinically-relevant manifestations15. Furthermore, it has recently been recognized that fibrosis appear to play a driving role in the development of AF5.
At the genetic level, several structural genes have been found to be implicated in both AF and cardiomyopathy. Peng et al. found an association between rare loss-of-function variants in the MYL4 gene and atrial cardiomyopathy. These rare variants were found to cause atrial fibrosis leading to atrial cardiomyopathy and atrial arrhythmia16. Furthermore, Gudbjartsson et al. identified a frameshift variant in MYL4 associated with a recessive form of AF, suggesting a genetic overlap between AF and cardiomyopathy5.
Another important structural gene, TTN, is strongly linked to AF and also associated with cardiomyopathy. This gene encodes a giant sarcomere protein (titin). Titin-truncating variants (TTNtv) have been shown to predispose directly to lone AF17. TTNtv were found to be significantly enriched within families diagnosed with AF and lone AF patients. Interestingly, TTNtv are known to occur in 15 % of dilated cardiomyopathy (DCM) cases and represent the most common genetic cause of DCM18. A CRISPR-Cas9 mutant zebrafish carrying a mutation in the homologue gene ttn in zebrafish, revealed increased amount of fibrosis, particularly in atria of the mutant fish, suggesting a predisposition for AF and in general arrhythmia and conduction disease17. Previous studies have demonstrated a higher degree of re-entry activity in patients with atrial fibrosis, which suggest a likely explanation for the development AF in these patients19.
Both TTNtv and MYL4 constitutes components of the cardiac sarcomere. Titin is the giant protein that connect the thick filament to the sarcomere, whereas myosin light chains constitutes a part of the thick filament. The bands of the cardiac sarcomere are due to the overlap of thin and thick filaments. Abnormalities of the sarcomere are directly linked to causing cardiomyopathy and the majority of HCM cases are a result of these abnormal protein structures20.
Findings of compromised sarcomere structure in both TTN and MYL4 variants as well as increased atrial fibrosis in zebrafish with TTNtv suggest an essential role of structural genes in both AF and atrial cardiomyopathy. The relationship is complex, but identifying genetic subtypes of cardiomyopathy and their associations with AF might help to expand our understanding of the pathophysiology of AF and speed up the implementation of personized medicine.
Table 1. Examples of the most common structural genes associated with cardiomyopathy21,22,16, 18.
|Gene||Protein||Chromosome location||Type of cardiomyopathy|
|MYL4||Myosin light chain||Chr17||Atrial cardiomyopathy|
|MYH7||Myosin heavy chain||Chr14||HCM|
|MYBPC3||Myosin binding protein C||Chr11||HCM|
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