BACKGROUND: Atrial Fibrillation (AF), the most common cardiac arrhythmia, is a significant public health problem in the United States, affecting approximately 2.2 million Americans. Recently, several chromosomal loci and genes have been found to be associated with familial AF. However, in most other AF cases, the genetic basis is still poorly understood. OBJECTIVE: The purpose of this study was to investigate the molecular basis of familial AF in a Dutch kindred group. METHODS: We analyzed a four-generation Dutch family in which AF segregated as an autosomal dominant trait. After the exclusion of linkage to 10q22-24, 6q14-16, 5p13, KCNQ1, KCNE2, KCNJ2 and some ion-channel-associated candidate genes, a genome-wide linkage scan using 398 microsatellite markers was performed. RESULTS: Two-point logarithms of odds (LOD) scores >1 at recombination fraction [theta] = 0.00 and a haplotype segregating with the disorder were demonstrated only across regions of chromosome 10. Subsequent fine mapping gave a maximum two-point LOD score of 4.1982 at D10S568 at [theta] = 0.00. Distinct recombination in several individuals narrowed the shared region among all affected individuals to 16.4 cM on the Genethon map (flanking markers: D10S578 and D10S1652), which corresponds to chromosome 10p11-q21. Thirteen candidate genes residing in this region, which could be associated with AF, were screened. No mutation has been found in their coding regions including the intron splice regions. CONCLUSION: We identify a novel locus for AF on chromosome 10p11-q21, which provides further evidence of genetic heterogeneity in this arrhythmia.
BACKGROUND:Atrial Fibrillation (AF), the most common cardiac arrhythmia, is a significant public health problem in the United States, affecting approximately 2.2 million Americans. Recently, several chromosomal loci and genes have been found to be associated with familial AF. However, in most other AF cases, the genetic basis is still poorly understood. OBJECTIVE: The purpose of this study was to investigate the molecular basis of familial AF in a Dutch kindred group. METHODS: We analyzed a four-generation Dutch family in which AF segregated as an autosomal dominant trait. After the exclusion of linkage to 10q22-24, 6q14-16, 5p13, KCNQ1, KCNE2, KCNJ2 and some ion-channel-associated candidate genes, a genome-wide linkage scan using 398 microsatellite markers was performed. RESULTS: Two-point logarithms of odds (LOD) scores >1 at recombination fraction [theta] = 0.00 and a haplotype segregating with the disorder were demonstrated only across regions of chromosome 10. Subsequent fine mapping gave a maximum two-point LOD score of 4.1982 at D10S568 at [theta] = 0.00. Distinct recombination in several individuals narrowed the shared region among all affected individuals to 16.4 cM on the Genethon map (flanking markers: D10S578 and D10S1652), which corresponds to chromosome 10p11-q21. Thirteen candidate genes residing in this region, which could be associated with AF, were screened. No mutation has been found in their coding regions including the intron splice regions. CONCLUSION: We identify a novel locus for AF on chromosome 10p11-q21, which provides further evidence of genetic heterogeneity in this arrhythmia.
Authors: Stefan Kääb; Dawood Darbar; Charlotte van Noord; Josée Dupuis; Arne Pfeufer; Christopher Newton-Cheh; Renate Schnabel; Seiko Makino; Moritz F Sinner; Prince J Kannankeril; Britt M Beckmann; Subbarao Choudry; Brian S Donahue; Jan Heeringa; Siegfried Perz; Kathryn L Lunetta; Martin G Larson; Daniel Levy; Calum A MacRae; Jeremy N Ruskin; Annette Wacker; Albert Schömig; H-Erich Wichmann; Gerhard Steinbeck; Thomas Meitinger; André G Uitterlinden; Jacqueline C M Witteman; Dan M Roden; Emelia J Benjamin; Patrick T Ellinor Journal: Eur Heart J Date: 2009-01-13 Impact factor: 29.983
Authors: Saumya Das; Seiko Makino; Yonathan F Melman; Marisa A Shea; Sanjeev B Goyal; Anthony Rosenzweig; Calum A Macrae; Patrick T Ellinor Journal: Heart Rhythm Date: 2009-04-15 Impact factor: 6.343