Publications

2023

1. EP Europace

   

   Copy number variation of gasdermin D gene is associated with atrial fibrillation-related thromboembolic stroke

   Pang-Shuo Huang, Jen-Fang Cheng, Guan-Wei Li , and 7 more authors

   EP Europace, Apr 2023

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   Atrial fibrillation (AF) is one of the major causes of ischaemic stroke. In addition to clinical risk evaluated by the CHA2DS2-VASC score, the impact of genetic factors on the risk of AF-related thromboembolic stroke has been largely unknown. We found several copy number variations (CNVs) in novel genes that were associated with thromboembolic stroke risk in our AF patients by genome-wide approach. Among them, the gasdermin D (GSDMD) gene was related to inflammation. We aimed to test whether GSDMD deletion was associated with AF-related stroke.A total of 400 patients with documented non-familial AF were selected, of which 100 patients were diagnosed with ischaemic stroke. The baseline characteristics of age, sex, valvular heart disease, coronary artery disease, heart failure, and CHA2DS2-VASc scores were not statistically different between cases and controls. We found that individuals who carried GSDMD homozygous deletion genotype had a higher risk for ischaemic stroke (odds ratio 2.195; 95\% confidence interval, 1.24–3.90; P = 0.007), even adjusted by CHA2DS2-VASc scores. We also validated the association of GSDMD with AF stroke in a large Caucasian population (UK Biobank).We found a link between the homozygous deletion of the GSDMD gene and an increased risk of stroke in patients with AF. This may implicate the use of therapy targeting GSDMD in the prevention of ischaemic stroke for AF patients.

   @article{10.1093/europace/euad103,
     author = {Huang, Pang-Shuo and Cheng, Jen-Fang and Li, Guan-Wei and Chuang, Eric Y and Chen, Jien-Jiun and Chiu, Fu-Chun and Wu, Cho-Kai and Wang, Yi-Chih and Hwang, Juey-Jen and Tsai, Chia-Ti},
     title = {{Copy number variation of gasdermin D gene is associated with atrial fibrillation-related thromboembolic stroke}},
     journal = {EP Europace},
     volume = {25},
     number = {5},
     pages = {euad103},
     year = {2023},
     month = apr,
     issn = {1099-5129},
     doi = {10.1093/europace/euad103},
     url = {https://doi.org/10.1093/europace/euad103},
     eprint = {https://academic.oup.com/europace/article-pdf/25/5/euad103/50487598/euad103.pdf},
   }

2. EP medRxiv

   

   Identification of two new genetic loci associated with atrial fibrillation in the Taiwanese population-implication of metabolism and fibrosis in atrial fibrillation mechanism

   Guan-Wei Lee, Jien-Jiun Chen, Sheng-Nan Chang , and 4 more authors

   medRxiv, Apr 2023

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   Background Genome-wide association studies (GWASs) have identified common single nucleotide polymorphisms (SNPs) in more than 100 genomic regions associated with atrial fibrillation (AF). Genes for AF identified by GWAS in the Caucasian populations may show ethnic differences in the Asian populations. We sought to identify other novel AF genes in the Taiwanese population by multi-stage GWAS.Methods In exploratory stage, GWAS with whole genome genotypes (4,512,191 SNPs) were done in 516 young AF Patients (58.1\textpm8.7 years-old, 438 men [84.9%]) from the National Taiwan University AF registry (NTUAFR) and 5160 normal sinus rhythm controls (57.8 \textpm8.7 years-old, 2460 men [47.7%]) from Taiwan Biobank. Significant loci were replicated in 1002 independent AF patients and 2003 NSR controls, and also in UK biobank (5630 AF cases and 24000 NSR controls). Quantitative trait locus mapping was performed to implicate functional significance.Results Stage I GWAS revealed 3 loci associated with AF with the genome-wide significance level, which included locus close to previously reported PITX2 gene (chromosome 4q25, rs2723329, P=1.53\texttimes10-10) and two novel loci close to RAP1A and HNF4G genes (chromosome 1p13.2, rs7525578, P= 1.24\texttimes10-26; chromosome 8q21.13, rs2980218, P=2.19\texttimes10-9, respectively). They were further validated in a stage II replication population (P=4.60\texttimes10-9, 4.45\texttimes10-10 and 6.97\texttimes10-5 for RAP1A, PITX2 and HNF4G, respectively). These 3 genes were also validated in the UK population. These 3 significant SNPs also show significant association with tissue expressions (RAP1A expression in thyroid, PITX2 in testicular, and HNF4G in lymphocyte tissues, respectively).Conclusions GWAS in Taiwan revealed previously reported PITX2 and two novel AF genes (RAP1A and HNF4G) with the most significant locus in RAP1A. RAP1A and HNF4G genes may implicate fibrosis and metabolic pathways, respectively, in the mechanism of AF.Competing Interest StatementThe authors have declared no competing interest.Funding StatementnoneAuthor DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Institutional Review Board (IRB) of the National Taiwan University Hospital (200911002RI confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

   @article{Lee2023.06.15.23291466,
     author = {Lee, Guan-Wei and Chen, Jien-Jiun and Chang, Sheng-Nan and Chiu, Fu-Chun and Huang, Pang-Shuo and Chuang, Eric Y. and Tsai, Chia-Ti},
     title = {Identification of two new genetic loci associated with atrial fibrillation in the Taiwanese population-implication of metabolism and fibrosis in atrial fibrillation mechanism},
     elocation-id = {2023.06.15.23291466},
     year = {2023},
     doi = {10.1101/2023.06.15.23291466},
     publisher = {Cold Spring Harbor Laboratory Press},
     url = {https://www.medrxiv.org/content/early/2023/06/20/2023.06.15.23291466},
     eprint = {https://www.medrxiv.org/content/early/2023/06/20/2023.06.15.23291466.full.pdf},
     journal = {medRxiv},
   }