Atrial fibrillation (AF) is the most common sustained arrhythmia, reaching epidemic proportions in the aging U.S. population and resulting in significant morbidity, mortality, and socioeconomic burden. Preliminary studies indicate that idiopathic or lone AF is familial in at least 15% of patients, highlighting the importance of genetic factors in the pathogenesis of this disorder. The overall objective of this study is to identify genes for AF by linkage and mutational analyses.
The first aim i s to determine the chromosomal location of AF genes by genome-wide linkage analyses. Mapping studies will be carried out in 4 large families with autosomal dominant AF in which linkage to known loci for AF have been excluded.
The second aim i s to identify mutations in candidate genes for AF based on chromosomal location, cardiac expression, and physiological rationale. Novel genes, once identified, will be screened for additional inherited and de novo mutations in a cohort of 154 unrelated patients with familial and sporadic AF.
The third aim i s to determine the frequency and spectrum of heritable ion channel and nuclear membrane defects in racially-diverse cohorts with lone AF. The long-term objectives of this work are to gain new insights into molecular mechanisms of arrhythmogenesis and to improve prediction, prevention, and treatment of AF.
| Brauch, Katharine M; Chen, Lin Y; Olson, Timothy M (2009) Comprehensive mutation scanning of LMNA in 268 patients with lone atrial fibrillation. Am J Cardiol 103:1426-8 |
| Chen, Lin Y; Herron, Kathleen J; Tai, Bee C et al. (2008) Lone atrial fibrillation: influence of familial disease on gender predilection. J Cardiovasc Electrophysiol 19:802-6 |
| Hodgson-Zingman, Denice M; Karst, Margaret L; Zingman, Leonid V et al. (2008) Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation. N Engl J Med 359:158-65 |
| Karst, Margaret L; Herron, Kathleen J; Olson, Timothy M (2008) X-linked nonsyndromic sinus node dysfunction and atrial fibrillation caused by emerin mutation. J Cardiovasc Electrophysiol 19:510-5 |
| Chen, L Y; Ballew, J D; Herron, K J et al. (2007) A common polymorphism in SCN5A is associated with lone atrial fibrillation. Clin Pharmacol Ther 81:35-41 |
| Olson, Timothy M; Alekseev, Alexey E; Moreau, Christophe et al. (2007) KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation. Nat Clin Pract Cardiovasc Med 4:110-6 |
| Olson, Timothy M; Alekseev, Alexey E; Liu, Xiaoke K et al. (2006) Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum Mol Genet 15:2185-91 |
