Genome-wide screening identifies a KCNIP1 copy number variant as a genetic predictor for atrial fibrillation

Tsai, Chien-Hung; Hsieh, Chia Shan; Chang, Sheng Nan; Chuang, Eric Y.; Ueng, Kwo Chang; Tsai, Chia Fen; Lin, Tsung-Hsien; Wu, Cho Kai; Lee, Jen Kuang; Lin, Lian Yu; Wang, Yi Chih; Yu, Chih Chieh; Lai, Ling‐Ping; Tseng, Chuen Den; Hwang, Juey Jen; Chiang, Fu-Tien; Lin, Jiunn Lee

doi:10.1038/ncomms10190

Cited by 39 publications

(32 citation statements)

References 41 publications

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“…The extraction and quantification of mRNA by means of reverse transcription polymerase chain reaction (RT-PCR) were performed as our standard protocols [32]. The RNA was then converted to complementary DNA by reverse transcription with random hexanucleotides and avian myeloblastosis virus reverse transcriptase (Boehringer, Mannheim, Germany).…”

Section: Methodsmentioning

confidence: 99%

Global Expression Profiling Identifies a Novel Hyaluronan Synthases 2 Gene in the Pathogenesis of Lower Extremity Varicose Veins

Hsieh

Tsai

Chen

et al. 2018

JCM

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Lower extremities varicose veins (VV) are among the most easily recognized venous abnormalities. The genetic mechanism of VV is largely unknown. In this study, we sought to explore the global expressional change of VV and identify novel genes that might play a role in VV. We used next-generation ribonucleic acid (RNA) sequence (RNA seq) technology to study the global messenger RNA expressional change in the venous samples of five diseased and five control patients. We identified several differentially expressed genes, which were further confirmed by conventional reverse transcription polymerase chain reaction (RT-PCR). Using these significant genes we performed in silico pathway analyses and found distinct transcriptional networks, such as angiogenesis, cell adhesion, vascular injury, and carbohydrate metabolisms that might be involved in the mechanism of VV. Among these significant genes, we also found hyaluronan synthases 2 gene (HAS2) played a pivotal role and governed all these pathways. We further confirmed that HAS2 expression was decreased in the venous samples of patients with VV. Finally, we used a zebrafish model with fluorescence emitting vasculature and red blood cells to see the morphological changes of the venous system and blood flow. We found that HAS2 knockdown in zebrafish resulted in dilated venous structural with static venous flow. HAS2 may modulate the transcriptional networks of angiogenesis, cell adhesion, vascular injury, and carbohydrate metabolisms in venous tissues and downregulation of HAS2 may underlie the mechanism of VV.

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Section: Methodsmentioning

confidence: 99%

Global Expression Profiling Identifies a Novel Hyaluronan Synthases 2 Gene in the Pathogenesis of Lower Extremity Varicose Veins

Hsieh

Tsai

Chen

et al. 2018

JCM

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“…First, the case number of patients with AF and thromboembolic stroke is low in our study. In our previous study [29], we demonstrated that significant disease-associating CNVs could be identified in samples with a case number as low as 100 patients. Nevertheless, our results should be replicated and validated in larger populations and in other ethnic populations.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Copy Number Variation Association Study of Atrial Fibrillation Related Thromboembolic Stroke

Hsieh

Huang

Chang

et al. 2019

JCM

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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.

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“…Consistent with its expression pattern, the knockdown of SGOL1 in zebrafish embryos resulted in bradycardia confirming the involvement of SGOL1 in heart rhythm control ( 86 ). KCNIP1 (potassium voltage-gated channel interacting protein 1) is another example of a gene that could be linked by whole genome analysis to heart disease, here atrial fibrillation (AF) ( 82 ). Interestingly, the reported mutation does not lead to a loss of function, but is suggested to increase KCNIP1 levels.…”

Section: Gwa Studies and Functional Genomics In Zebrafish: A Powerfulmentioning

confidence: 99%

“…Interestingly, the reported mutation does not lead to a loss of function, but is suggested to increase KCNIP1 levels. The authors modeled this by the overexpression of KCNIP1 in zebrafish and could show that increased KCNIP1 levels can result in transient atrial tachycardia and AF during high-rate pacing ( 82 ). Norton et al ( 79 ) identified BAG3 (Bcl-2 associated anthanogene 3) as a DCM-associated gene and could confirm its disease relevance by knocking-down BAG3 in zebrafish embryos.…”

Section: Gwa Studies and Functional Genomics In Zebrafish: A Powerfulmentioning

confidence: 99%

Genetics of Cardiovascular Disease: Fishing for Causality

Paone

Diofano

Park

et al. 2018

Front. Cardiovasc. Med.

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Cardiovascular disease (CVD) is still the leading cause of death in all western world countries and genetic predisposition in combination with traditional risk factors frequently mediates their manifestation. Genome-wide association (GWA) studies revealed numerous potentially disease modifying genetic loci often including several SNPs and associated genes. However, pure genetic association does not prove direct or indirect relevance of the modifier region on pathogenesis, nor does it define within the associated region the exact genetic driver of the disease. Therefore, the relevance of the identified genetic disease associations needs to be confirmed either in monogenic traits or in experimental in vivo model system by functional genomic studies. In this review, we focus on the use of functional genomic approaches such as gene knock-down or CRISPR/Cas9-mediated genome editing in the zebrafish model to validate disease-associated genomic loci and to identify novel cardiovascular disease genes. We summarize the benefits of the zebrafish for cardiovascular research and highlight examples demonstrating the successful combination of GWA studies and functional genomics in zebrafish to broaden our knowledge on the genetic and molecular underpinnings of cardiovascular diseases.

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Genome-wide screening identifies a KCNIP1 copy number variant as a genetic predictor for atrial fibrillation

Cited by 39 publications

References 41 publications

Global Expression Profiling Identifies a Novel Hyaluronan Synthases 2 Gene in the Pathogenesis of Lower Extremity Varicose Veins

Global Expression Profiling Identifies a Novel Hyaluronan Synthases 2 Gene in the Pathogenesis of Lower Extremity Varicose Veins

Genome-Wide Copy Number Variation Association Study of Atrial Fibrillation Related Thromboembolic Stroke

Genetics of Cardiovascular Disease: Fishing for Causality

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