Hereditary Component of Atrial Fibrillation Revealed

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:

Map of atrial activation

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• Review of genealogic and medical records of a 6-generation family revealed progressive sinus node dysfunction and AF restricted to 4 males related through maternal lineages. Suspecting a sex-linked basis for the disorder, targeted X chromosome genotyping mapped the disease locus to chromosome Xq28. This step led to discovery of a single amino acid deletion in the nuclear protein emerin, which impaired its localization to the nuclear membrane. Unlike prototypical null mutations in emerin that underlie Emery-Dreifuss muscular dystrophy, this unique mutation caused a cardioselective phenotype without skeletal muscle involvement.
• In a different family with 11 clinically affected members, AF was inherited as an autosomal dominant trait. A genome-wide mapping study localized the culprit gene to chromosome 1p36-p35, leading to identification of a frameshift mutation in the atrial natriuretic peptide (ANP) gene that segregated with AF. The mutation resulted in a circulating chimeric peptide, made up of ANP with an anomalous 12–amino acid tail, that shortened the atrial action potential in an isolated heart model. Discovery of mutant ANP thus uncovered an unexpected association between a defective hormone and susceptibility to arrhythmia.

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:

• Discover novel genes for AF
• Gain new insights into the pathogenic mechanisms of this common arrhythmia
• Develop, ultimately, improved diagnostic, therapeutic, and preventive strategies