Abstract
Atrial fibrillation (AF) is a common cardiac arrhythmia and is one of the major causes of ischemic stroke. In addition to the clinical factors such as CHADS2 or CHADS2-VASC score, the impact of genetic factors on the risk of thromboembolic stroke in patients with AF has been largely unknown. Single-nucleotide polymorphisms in several genomic regions have been found to be associated with AF. However, these loci do not contribute to all the genetic risks of AF or AF related thromboembolic risks, suggesting that there are other genetic factors or variants not yet discovered. In the human genome, copy number variations (CNVs) could also contribute to disease susceptibility. In the present study, we sought to identify CNVs determining the AF-related thromboembolic risk. Using a genome-wide approach in 109 patients with AF and thromboembolic stroke and 14,666 controls from the Taiwanese general population (Taiwan Biobank), we first identified deletions in chromosomal regions 1p36.32-1p36.33, 5p15.33, 8q24.3 and 19p13.3 and amplifications in 14q11.2 that were significantly associated with AF-related stroke in the Taiwanese population. In these regions, 148 genes were involved, including several microRNAs and long non-recoding RNAs. Using a pathway analysis, we found deletions in GNB1, PRKCZ, and GNG7 genes related to the alpha-adrenergic receptor signaling pathway that play a major role in determining the risk of an AF-related stroke. In conclusion, CNVs may be genetic predictors of a risk of a thromboembolic stroke for patients with AF, possibly pointing to an impaired alpha-adrenergic signaling pathway in the mechanism of AF-related thromboembolism.
Highlights
Atrial fibrillation (AF) is a common cardiac arrhythmia in the general population, and causes much morbidity and mortality [1]
A genome-wide detection of copy number variations (CNVs) was performed in 109 patients with AF and thromboembolic stroke and 14,666 controls, using the Axiom Genome-Wide Taiwan Biobank (TWB) Array Plate (653,291 markers) to obtain single nucleotide polymorphisms (SNP) and allelic fluorescence intensities and to generate CNV calls and determine copy number
The most serious complication of AF is the thromboembolic stroke, which occurs with increasing frequency when risk factors, either clinical or genetic risk factors, accumulate
Summary
Atrial fibrillation (AF) is a common cardiac arrhythmia in the general population, and causes much morbidity and mortality [1]. The impact of genetic factors or polymorphisms on the risk of thromboembolic stroke in patients with AF has been largely unknown. We have shown that the angiotensinogen gene and CRP gene genetic polymorphisms could predict the risk of stroke for patients with AF [4,5]. It has been demonstrated that both single nucleotide polymorphisms (SNP)s and CNVs contribute to disease susceptibility [6]. Examining both SNP and CNV variants is important to determine the genetic causes of complex human phenotypes and diseases
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