Mutational spectrum of the GATA5 gene associated with familial atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia seen in clinical practice, with an estimated prevalence of 1-2% in the general population. The incidence of AF increases dramatically with age, ranging from less than 1% in patients under 60 years of age to almost 10% in those aged 80 and over (1). AF is associated with substantial morbidity, mortality and health care burden. AF confers a five-fold increased risk of stroke, and about 15-20% of all strokes result from this tachycardia. AF also accounts for an approximately two-fold increase in risk of death, and a third of all hospitalizations for cardiac rhythm disturbances (1-3). AF frequently arises from diverse cardiac and systemic disorders, including hypertension, coronary artery disease, valvular heart disease, and hyperthyroidism (1). However, in 30% to 45% of AF cases, an underlying cause cannot be detected by routine methods, a condition usually defined as idiopathic or lone AF, of which at least 15% have a positive family history, hence termed familial AF (1). There is now growing evidence demonstrating that genetic defects play an important role in the pathogenesis of AF and multiple genes involved in AF have been identified (4). Nevertheless, AF is genetically heterogeneous and the genetic determinants of AF remain largely unclear. Recent studies highlight a key role for several cardiac transcrip- tion factors, including NKX2-5, GATA4, GATA5 and GATA6, in the cardiogenesis (5,6), and mutations in NKX2-5, GATA4 and GATA6 have been causally implicated in congenital heart diseases and AF (7-12). GATA5 is another member of the GATA family, and its expression and functions overlap with those of GATA4 and GATA6 during cardiovascular development, especially in regulation of target gene expression synergistically with NKX2-5, which points to the likely association of functionally impaired GATA5 with AF (5,6). To assess the prevalence and spectrum of GATA5 mutations in patients with familial AF, 130 unrelated index patients with familial AF identified among the Chinese Han population were included in this study. The control population comprised 200 unrelated ethnically matched healthy individuals. All subjects were appraised by medical history, physical examination, electrocardiography, and echocardiogra- phy. The study subjects were clinically classified using a consistently applied set of definitions (10). The baseline demographic and clinical characteristics of the study population are summarized in Table 1 .T he study protocol was reviewed and approved by the local institutional ethics committee and written informed consent was obtained from all participants prior to study. Peripheral venous blood specimens were taken from all subjects and genomic DNA was extracted as described previously (10). According to the genomic DNA sequence of GATA5 (GenBank accession no. NT_011362), the primer sequences were designed as shown in Table 2. The coding exons (exons 2-7) and their flanking splice junction sites of GATA5 were screened for genetic variations by means of polymerase chain reaction, followed by DNA sequencing with Big Dye chemistry under an ABI 3130 XL DNA Analyzer.