ORPHA: 334; DO: 0050650;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16q22.2-q22.3 | {Atrial fibrillation 8, susceptibility to} | 613055 | Autosomal dominant | 3 | ZFHX3 | 104155 |
A number sign (#) is used with this entry because of evidence that susceptibility to familial atrial fibrillation-8 (ATFB8) is conferred by variation in the ZFHX3 gene (104155) on chromosome 16q22.
Atrial fibrillation is the most common sustained cardiac rhythm disturbance, affecting more than 2 million Americans, with an overall prevalence of 0.89%. The prevalence increases rapidly with age, to 2.3% between the ages of 40 and 60 years, and to 5.9% over the age of 65. The most dreaded complication is thromboembolic stroke (Brugada et al., 1997).
For a discussion of genetic heterogeneity of atrial fibrillation, see 608583.
Gudbjartsson et al. (2009) expanded the genomewide association study on atrial fibrillation in Iceland, which had identified risk variants on 4q25 (see 611494), and tested the most significant associations in samples from Iceland, Norway, and the United States. This sample consisted of 2,385 atrial fibrillation, or atrial flutter, cases and 33,752 controls who were genotyped using the Illumina HumanHap300 or HumanHapCNV370 bead chips. A variant in the ZFHX3 (104155) gene on chromosome 16q22, the T allele of single-nucleotide polymorphism (SNP) rs7193343, was associated significantly with atrial fibrillation (odds ratio 1.21, p = 1.4 x 10(-10)). This variant was also associated with ischemic stroke (see 601367; odds ratio = 1.11, p = 0.00054) and cardioembolic stroke (odds ratio = 1.22, p = 0.00021) in a combined analysis of 5 stroke samples. The association of rs7193343 with atrial fibrillation was not significant in a Han Chinese population from Hong Kong consisting of 286 atrial fibrillation cases and 2,763 controls. However, the T allele at rs7193343 is much more frequent in the Han Chinese population than in samples from persons of European descent (0.68 vs 0.14-1.20, respectively).
Benjamin et al. (2009) conducted a metaanalysis of genomewide association studies for atrial fibrillation in participants from 5 community-based cohorts. Metaanalyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) atrial fibrillation cases identified a locus for atrial fibrillation at chromosome 16q22 represented by the SNP rs2106261 located in an intron of the ZFHX3 gene (risk ratio of 1.19; p = 2.3 x 10(-7)). This association was replicated in an independent cohort from the German Atrial Fibrillation Network (odds ratio = 1.44; p = 1.6 x 10(-11); combined risk ratio for the 2 groups = 1.25; combined p = 1.8 x 10(-15)).
Jameson et al. (2023) defined the ATFB8 locus using SNPs in strong linkage disequilibrium with the previously identified ATFB8-associated SNP rs2106261, yielding a 74-kb region containing 52 common variants with a minor allele frequency greater than 1% in individuals of European descent. Intersecting the 52 ATFB-associated SNPs on 16q22 with the DNaseI hypersensitivity signal in human cardiomyocytes identified 6 candidate SNPs that overlapped with active chromatin marks. The authors then assessed the effect of the 6 candidates on gene expression in human pluripotent stem cell-derived cardiomyocytes (PSC-CMs), and found only 1 SNP (C-A, rs12931021; 104155.0002) that exhibited differential activity dependent on genotype, with the nonrisk C allele being 3.9-fold more active than the risk-associated A allele. Chromatin immunoprecipitation analysis in PSC-CMs confirmed the genotype-dependent regulatory activity at rs12931021. Using CRISPR-Cas9 to delete a 219-bp region harboring rs12931021 in PSC-CMs, the authors observed that the deleted cells expressed a significantly lower level of ZFHX3 than wildtype cells. In addition, analysis of isogenic PSC-CMs demonstrated a dose relationship between nonrisk C allele number and greater ZFHX3 expression. The authors concluded that ZFHX3 is the causal gene at the ATFB8 locus at 16q22, and that rs12931021 is a functional SNP mediating the genetic association with increased risk of atrial fibrillation correlated to reduced ZFHX3 expression.
Jameson et al. (2023) generated mice that were heterozygous or homozygous for cardiomyocyte-restricted loss of Zfhx3, and observed a high incidence of premature death in the mutant mice, at age 10 months in the knockout mice and 12 months in the heterozygotes, compared to wildtype littermates. Cardiac MRI at age 3 months showed a significantly reduced ejection fraction and significantly increased left atrial size in the knockout mice compared to controls. By 9 to 11 months of age, Zfhx3 knockout mice displayed massively dilated hearts with large thrombi in both the left and right atria and significantly increased fibrosis of the atrial wall and left ventricle. In addition, the mutant mice exhibited a premorbid phenotype indicating advanced heart failure, including diffuse edema/anasarca, abdominal distention presumably due to ascites, tachypnea, and muscle wasting. In vivo cardiac electrophysiology testing at age 3 months demonstrated a gene-dose response in inducible atrial arrhythmias by programmed stimulation in the mice, with the knockout mice having a higher incidence of atrial arrhythmias/atrial fibrillation than heterozygotes or wildtype mice. The knockout mice were also more prone to arrhythmia induction and showed an increased frequency of atrial arrhythmias. Ex vivo optical mapping in knockout mouse hearts demonstrated significantly slower right atrial conduction, and knockout left atrial cardiomyocytes showed abnormal calcium handling compared to wildtype. The authors concluded that loss of Zfhx3 causes conditions that predispose to increased automaticity, resulting in the observed increased susceptibility to atrial arrhythmias/atrial fibrillation.
Benjamin, E. J., Rice, K. M., Arking, D. E., Pfeufer, A., van Noord, C., Smith, A. V., Schnabel, R. B., Bis, J. C., Boerwinkle, E., Sinner, M. F., Dehghan, A., Lubitz, S. A., and 44 others. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nature Genet. 41: 879-881, 2009. [PubMed: 19597492] [Full Text: https://doi.org/10.1038/ng.416]
Brugada, R., Tapscott, T., Czernuszewicz, G. Z., Marian, A. J., Iglesias, A., Mont, L., Brugada, J., Girona, J., Domingo, A., Bachinski, L. L., Roberts, R. Identification of a genetic locus for familial atrial fibrillation. New Eng. J. Med. 336: 905-911, 1997. [PubMed: 9070470] [Full Text: https://doi.org/10.1056/NEJM199703273361302]
Gudbjartsson, D. F., Holm, H., Gretarsdottir, S., Thorleifsson, G., Walters, G. B., Thorgeirsson, G., Gulcher, J., Mathiesen, E. B., Njolstad, I., Nyrnes, A., Wilsgaard, T., Hald, E. M., and 31 others. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nature Genet. 41: 876-878, 2009. [PubMed: 19597491] [Full Text: https://doi.org/10.1038/ng.417]
Jameson, H. S., Hanley, A., Hill, M. C., Xiao, L., Ye, J., Bapat, A., Ronzier, E., Hall, A. W., Hucker, W. J., Clauss, S., Barazza, M., Silber, E., Mina, J. A., Tucker, N. R., Mills, R. W., Dong, J.-T., Milan, D. J., Ellinor, P. T. Loss of the atrial fibrillation-related gene, Zfhx3, results in atrial dilation and arrhythmias. Circ. Res. 133: 313-329, 2023. [PubMed: 37449401] [Full Text: https://doi.org/10.1161/CIRCRESAHA.123.323029]