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STATE-OF-THE-ART PAPER

Molecular Genetics of Atrial Fibrillation

Chia-Ti Tsai, MD, PhD^_*, Ling-Ping Lai, MD, PhD^_*,, Juey-Jen Hwang, MD, PhD^_*, Jiunn-Lee Lin, MD, PhD^_* and Fu-Tien Chiang, MD, PhD^_*,,_*

^_* Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
Institute of Pharmacology, National Taiwan University Hospital, Taipei, Taiwan
Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Manuscript received November 27, 2007; revised manuscript received January 29, 2008, accepted February 19, 2008.

^_* Reprint requests and correspondence: Dr. Fu-Tien Chiang, Department of Laboratory Medicine, National Taiwan University Hospital, No. 1, Section 1, Jen-Ai Road, Taipei 100, Taiwan. (Email: futienc{at}ntuh.gov.tw).

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. There is genetic predisposition for the development of AF. Recently, by linkage analysis, several loci have been mapped for monogenetic AF, including 11p15.5, 21q22, 17q, 7q35–36, 5p13, 6q14–16, and 10q22. Some of these loci encode for subunits of potassium channels (KCNQ1, KCNE2, KCNJ2, and KCNH2 genes), and the remaining are yet unidentified. All of the known mutations are associated with a gain of function of repolarization potassium currents, resulting in a shortening of action potential duration and atrial refractory period, which facilitate multiple re-entrant circuits in AF. In addition to familial AF, common AF often occurs in association with acquired diseases such as hypertension, valvular heart disease, and heart failure. By genetic association study, some genetic variants or polymorphisms related to the mechanism of AF have been found to be associated with common AF, including genes encoding for subunits of potassium or sodium channels, sarcolipin gene, renin-angiotensin system gene, connexin-40 gene, endothelial nitric oxide synthase gene, and interleukin-10 gene. These observations suggest that genes related to ionic channels, calcium handling protein, fibrosis, conduction and inflammation play important roles in the pathogenesis of common AF. The complete elucidation of genetic loci for common AF is still in its infancy. However, the availability of genomewide scans with hundreds or thousands of polymorphisms has made it possible. However, challenges and pitfalls exist in association studies, and consideration of particular features of study design is necessary before making definite conclusions from these studies.

Key Words: genetics • atrial fibrillation • familial • multifactorial

Abbreviations and Acronyms   AF = atrial fibrillation   CI = confidence interval   IKr = rapidly activating delayed rectifier potassium current   IKs = slowly activating delayed rectifier potassium current   IK1 = inward rectifier potassium current   LQTS = long QT syndrome   OR = odds ratio   RAS = renin-angiotensin system   SLN = sarcolipin   SNP = single nucleotide polymorphism

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