A Mayo Clinic study published in 2003 revealed that lone atrial fibrillation (AF) is a familial disorder in at least 15% of patients with AF, highlighting the pathogenic role of hereditary factors. The Human Genome Project, completed in the same year, has provided a comprehensive road map to facilitate discovery of the genetic underpinnings of AF.
Last year more than 2000 patients with AF were referred to the Mayo Clinic Heart Rhythm Center for evaluation and management of this arrhythmia. This large referral base has served as a rich resource for recruitment of familial cases of lone AF, under the auspices of an ongoing National Institutes of Health–sponsored study. The study cohort comprises more than 250 unrelated individuals with structurally normal hearts who lack traditional risk factors for AF. Their AF was diagnosed at a mean age of 44 years.
Initial investigations at Mayo and other research centers have implicated AF as a channelopathy in a subset of patients. Indeed, mutations within some of the same genes responsible for long QT syndrome and ventricular arrhythmia have been identified in patients with AF, indicating that distinct chamber-specific rhythm disorders could share similar genetic origins.
In vitro modeling of mutant channels showed that the extremes of atrial action potential shortening or lengthening were arrhythmogenic substrates for AF. Further investigations have revealed a synergistic gene-environment mechanism for AF and a common risk-conferring functional polymorphism.
Recruitment and phenotypic characterization of large, multigenerational families have enabled a powerful strategy for AF gene discovery that complements a direct candidate gene approach—linkage analysis. The ability to precisely map the genomic location of an unknown disease gene provides a unique opportunity to identify unsuspected molecular bases for AF. Two Mayo Clinic studies illustrate this point:
Collectively, research studies have established lone AF as a genetically heterogeneous disorder resulting from distinct molecular defects. Lone AF remains an idiopathic condition, however, in the vast majority of patients.
Under the direction of Timothy M. Olson, M.D., efforts are under way to: