Familial Aggregation of Atrial Fibrillation

Abstract

Background-Heritability may play a role in nonfamilial atrial fibrillation (AF). We hypothesized that a monozygotic (MZ) twin whose co-twin was diagnosed with AF would have an increased risk of the disease compared with a dizygotic (DZ) twin in the same situation. Methods and Results-A sample of 1137 same-sex twin pairs (356 MZ and 781 DZ pairs) in which one or both members were diagnosed with AF were identified in The Danish Twin Registry. Concordance rates were twice as high for MZ pairs than for DZ pairs regardless of sex (22.0% versus 11.6%, PϽ0.0001). In a Cox regression of event-free survival times, we compared the time span between occurrences of disease in MZ and DZ twins. The unaffected twin was included when his or her twin-sibling (the index twin) was diagnosed with AF. After adjustment for age at entry, MZ twins had a significantly shorter event-free survival time (hazard ratio, 2.0; 95% CI, 1.3 to 3.0), thereby indicating a genetic component. Using biometric models, we estimated the heritability of AF to be 62% (55% to 68%), due to additive genetics. There were no significant differences across sexes. Conclusions-All the analyses of twin similarities in the present study indicate that genetic factors play a substantial role in the risk of AF for both sexes. The recurrence risk for co-twins (12% to 22%) is clinically relevant and suggests that co-twins of AF-affected twins belong to a high-risk group for AF. (Circ Arrhythmia Electrophysiol. 2009;2:378-383.)

Atrial fibrillation: the role of common and rare genetic variants

“…6 A number of studies have demonstrated that AF and in particular lone AF have a substantial genetic component. [7][8][9][10][11][12][13] Oyen et al 14 have recently shown that an individual's risk of developing lone AF at a young age, increases drastically with both increasing number of relatives with lone AF and decreasing age at onset of the disease in these relatives, indicating an underlying genetic component in early onset lone AF.…”

A novel NKX2.5 loss-of-function mutation responsible for familial atrial fibrillation

“…; up to 15% of these cases have a positive family history, and are thus defined as familial AF (9). Increasing evidence demonstrates the familial aggregation of AF and an enhanced vulnerability to AF in the close relatives of patients with AF, suggesting that genetic defects may be involved in the pathogenesis of AF in a subset of patients (10)(11)(12)(13)(14)(15)(16). Genome-wide genetic linkage analysis with highly polymorphic microsatellite markers mapped susceptibility loci for AF on human chromosomes 10q22, 6q14-16, 11p15.5, 5p13, 10p11-q21 and 5p15, of which AF-causing mutations in two genes, KCNQ1 on chromosome 11p15.5 and NUP155 on chromosome 5p13, were identified and functionally characterized (17)(18)(19)(20)(21)(22)(23).…”

A novel GATA5 loss-of-function mutation underlies lone atrial fibrillation

“…However, in 30-45% of AF patients, no established risk factors are identified by routine procedures, and such AF is defined as 'idiopathic' or 'lone' (1), of which at least 15% have a positive family history, so termed familial AF (7). Growing evidence has documented the familial aggregation of AF and an enhanced susceptibility to AF in the close relatives of patients with AF, indicating that hereditary defects may play an important role in the pathogenesis of AF in a subset of patients (8)(9)(10)(11)(12)(13)(14). Genome-wide linkage analysis with polymorphic genetic markers mapped multiple susceptibility loci for AF on human chromosomes 10q22, 6q14-16, 11p15.5, 5p13, 10p11-q21 and 5p15, of which AF-causing mutations in 2 genes, KCNQ1 on chromosome 11p15.5 and NUP155 on chromosome 5p13, were identified and functionally characterized (15)(16)(17)(18)(19)(20)(21).…”