Atrial Fibrillation, Familial, 5

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Retrieved

2019-09-22

Source

Omim

Trials

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Genes

PITX2, NKX2-5, SCN2B, NKX2-6, SCN3B, ABCC9, KCNE2, NUP155, TTN, SCN5A, SCN4B, SCN1B, GATA4, NPPA, MYL4, KCNQ1, KCNJ2, KCNE1, KCNA5, GJA5, GATA6, GATA5

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Description

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.

Mapping

Gudbjartsson et al. (2007) performed a genomewide association scan followed by replication studies in 3 populations of European descent and a Chinese population from Hong Kong and found a strong association between 2 sequence variants on chromosome 4q25, rs2200733 and rs10033464, and atrial fibrillation. Gudbjartsson et al. (2007) showed that about 35% of individuals of European descent have at least one of the variants and that the risk of atrial fibrillation increases by 1.72 and 1.39 per copy, respectively. The association with rs2200733, the stronger variant, was replicated in the Chinese population, where it is carried by 75% of individuals and the risk of atrial fibrillation is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. No gene was known to be present in the linkage disequilibrium block containing these 2 variants. Both variants are adjacent to PITX2 (601542), which has a critical function in left-right asymmetry of the heart.

In a genomewide association study of 1,661 Icelandic patients with ischemic stroke (601367) and 10,815 control subjects, combined with replication in 2 sets of European samples comprising 2,224 cases and 2,583 controls, Gretarsdottir et al. (2008) found a significant association between the cardioembolic subtype of ischemic stroke and rs2200733 (odds ratio of 1.54; p = 8.05 x 10(-9)). No other variant was associated with ischemic stroke in general or the subtypes of stroke due to large artery atherosclerosis or small-vessel disease. In all sample sets combined, rs2200733 was associated with ischemic stroke (combined OR of 1.26; p = 2.18 x 10(-10)), and both rs2200733 and rs10033464 associated strongly with cardioembolic stroke (OR of 1.52; p = 5.8 x 10(-12) and OR of 1.27; p = 6.1 x 10(-4), respectively). For rs10033464, which conferred a more modest association with atrial fibrillation, the association with ischemic stroke was not significant. These data were in line with the well-established role of atrial fibrillation in the risk for cardioembolic stroke.

Benjamin et al. (2009) performed a metaanalysis of genomewide association studies for atrial fibrillation in participants from 5 community-based cohorts. They replicated association with the chromosome 4q25 locus, finding significant association for the SNP rs17042171 150 kb telomeric to the transcription factor PITX2 gene (combined relative risk of 1.65, P = 3.9 x 10(-63)).

Gudbjartsson et al. (2009) expanded their initial genomewide association study in Iceland on atrial fibrillation, increasing the sample size to 2,385 atrial fibrillation cases and 33,752 controls who were genotyped using the Illumina HumanHap300 or HumanHapCNV370 bead chips. Of the 10 SNPs showing the strongest association, the 7 most significant variants corresponded to the signal on chromosome 4q25.

In a case-control study involving 383 Chinese Han patients with atrial fibrillation (AF) and 851 Chinese Han controls, Shi et al. (2009) analyzed rs2200733 and found highly significant association with AF (p = 3.7 x 10(-11); OR, 1.81). The association was stronger for lone AF than for AF associated with other cardiovascular disease (OR, 2.40 and p = 1.3 x 10(-9) vs OR, 1.59 and p = 6.2 x 10(-7)). Shi et al. (2009) also studied 811 Chinese Han patients with ischemic stroke and 688 Chinese Han controls, but found no significant association between rs2200733 and ischemic stroke. Noting that the risk allele T is more common in the Chinese population than in Caucasians (greater than 50% compared to less than 30%, respectively), Shi et al. (2009) suggested that rs2200733 is a more common genetic risk factor in the Chinese population than in Caucasian populations.

In a metaanalysis of genomewide association studies conducted using 1,335 individuals with lone atrial fibrillation and 12,844 unaffected individuals, Ellinor et al. (2010) confirmed association on chromosome 4q25; the most significant SNP was rs6843082 (odds ratio, 2.03; p = 2.5 x 10(-28)).

Molecular Genetics

Ye et al. (2016) identified a functional SNP, rs2595104, within the ATFB5 locus identified by Gudbjartsson et al. (2007) on chromosome 4q25. The SNP lies within intron 3 and intron 4 of isoforms PITX2a and PITX2b, respectively, and approximately 10 kb upstream of the transcription start site of PITX2c, the dominant isoform in developing and adult left atrium. Ye et al. (2016) showed that rs2595104 alters PITX2c expression via interaction with the transcription factor TFAP2A (107580), and hypothesized that this pathway could ultimately contribute to atrial fibrillation susceptibility at the 4q25 locus. See PITX2 (601542).