ArticlePLoS genetics2015
Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation.
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Article in PLoS genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers, 2 of them syntheses that pooled it.
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35citing papers in PubMed, 2 pooled it
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
35 citing papers in PubMed, 2 syntheses or guidelines pooled it, 57 citations in OpenAlex.
- Pooled it
- Gene-gene Interaction Analyses for Atrial Fibrillation.Scientific reports · 2016Pooled it
- LncRNA-induced lysosomal localization of NHE1 promotes increased lysosomal pH in macrophages leading to atherosclerosis.The Journal of biological chemistry · 2025Article
- A Discussion of the Contemporary Prediction Models for Atrial Fibrillation.Medical research archives · 2023Article
- Loss of the Atrial Fibrillation-Related Gene,Circulation research · 2023Article
- Gene Polymorphism and Recurrent Atrial Fibrillation after Catheter Ablation: A Comprehensive Review.Reviews in cardiovascular medicine · 2023Review
- Transcriptomics-based network medicine approach identifies metformin as a repurposable drug for atrial fibrillation.Cell reports. Medicine · 2022Article
- Decoding the PITX2-controlled genetic network in atrial fibrillation.JCI insight · 2022Article
- Zfhx3 Transcription Factor Represses the Expression ofInternational journal of molecular sciences · 2021Article
- A narrative review of non-coding RNAs in atrial fibrillation: potential therapeutic targets and molecular mechanisms.Annals of translational medicine · 2021Review
- Transcriptional factors in calcium mishandling and atrial fibrillation development.Pflugers Archiv : European journal of physiology · 2021Review
- Angiogenic factor AGGF1 acts as a tumor suppressor by modulating p53 post-transcriptional modifications and stability via MDM2.Cancer letters · 2021Article
- Association between ZFHX3 and PRRX1 Polymorphisms and Atrial Fibrillation Susceptibility from Meta-Analysis.International journal of hypertension · 2021Article
- A Novel Mapping Strategy Utilizing Mouse Chromosome Substitution Strains Identifies Multiple Epistatic Interactions That Regulate Complex Traits.G3 (Bethesda, Md.) · 2020Article
- Vascular smooth muscle cell phenotypic transition regulates gap junctions of cardiomyocyte.Heart and vessels · 2020Article
- Investigation of gene-gene interactions in cardiac traits and serum fatty acid levels in the LURIC Health Study.PloS one · 2020Article
- Identification of rare variants in cardiac sodium channel β4-subunit gene SCN4B associated with ventricular tachycardia.Molecular genetics and genomics : MGG · 2019Article
- SUMOylation of Vps34 by SUMO1 promotes phenotypic switching of vascular smooth muscle cells by activating autophagy in pulmonary arterial hypertension.Pulmonary pharmacology & therapeutics · 2019Article
- Lamin A mutation impairs interaction with nucleoporin NUP155 and disrupts nucleocytoplasmic transport in atrial fibrillation.Human mutation · 2019Article
- Atrial Fibrillation Genetics Update: Toward Clinical Implementation.Frontiers in cardiovascular medicine · 2019Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
50 authors at 9 institutions in 2 countries.
Yufeng HuangKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Chuchu WangKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Yufeng YaoKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Xiaoyu ZuoSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Shanshan ChenKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Chengqi XuKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Hongfu ZhangKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Qiulun LuKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Le ChangKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Fan WangKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Pengxia WangKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Rongfeng ZhangDepartment of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Zhenkun HuKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Qixue SongKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Xiaowei YangKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Cong LiKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Sisi LiKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Yuanyuan ZhaoKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Qin YangKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Dan YinKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Xiaojing WangKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Wenxia SiKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Xiuchun LiKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Xin XiongKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Dan WangKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Yuan HuangKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Chunyan LuoKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Jia LiKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Jingjing WangKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Jing ChenKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Longfei WangKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Li WangKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Meng HanKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Jian YeKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Feifei ChenDepartment of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Jingqiu LiuDepartment of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Ying LiuDepartment of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Gang WuDepartment of Cardiology, People's Hospital, Wuhan University, Wuhan, China.
Bo YangDepartment of Cardiology, People's Hospital, Wuhan University, Wuhan, China.
Xiang ChengDepartment of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
Yuhua LiaoDepartment of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
Yanxia WuDepartment of Cardiology, the First Affiliated Hospital of Wuhan City, Wuhan, China.
Tie KeKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Qiuyun ChenCenter for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America; Department of Molecular Medicine, Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America.
Xin TuKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Robert ElstonDepartment of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
Shaoqi RaoInstitute of Medical Systems Biology and Department of Medical Statistics and Epidemiology, School of Public Health, Guangdong Medical College, Dongguan, China.
Yanzong YangDepartment of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Yunlong XiaDepartment of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Qing K WangKey Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America; Department of Molecular Medicine, Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America.
Huazhong University of Science and Technology · CNFirst Affiliated Hospital of Dalian Medical University · CNCase Western Reserve University · USDalian Medical University · CNWuhan University · CNGuangdong Medical College · CNSun Yat-sen University · CNUniversity School · USWuhan No.1 Hospital · CN
Funding
NGS in Large CAD Families: In-Depth Identification of Rare Risk Genomic VariantsR01HL121358 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI WANG, QING KENNETH · 2014 to 2017
$2.8MTargeting Nav1.5 trafficking as a therapy for lethal genetic cardiac arrhythmiasR01HL126729 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI WANG, QING KENNETH · 2015 to 2018
$1.6MNHLBI NIH HHS R01 HL121358NHLBI NIH HHS R01 HL126729
Abstract
Atrial fibrillation (AF) is the most common cardiac arrhythmia at the clinic. Recent GWAS identified several variants associated with AF, but they account for <10% of heritability. Gene-gene interaction is assumed to account for a significant portion of missing heritability. Among GWAS loci for AF, only three were replicated in the Chinese Han population, including SNP rs2106261 (G/A substitution) in ZFHX3, rs2200733 (C/T substitution) near PITX2c, and rs3807989 (A/G substitution) in CAV1. Thus, we analyzed the interaction among these three AF loci. We demonstrated significant interaction between rs2106261 and rs2200733 in three independent populations and combined population with 2,020 cases/5,315 controls. Compared to non-risk genotype GGCC, two-locus risk genotype AATT showed the highest odds ratio in three independent populations and the combined population (OR=5.36 (95% CI 3.87-7.43), P=8.00×10-24). The OR of 5.36 for AATT was significantly higher than the combined OR of 3.31 for both GGTT and AACC, suggesting a synergistic interaction between rs2106261 and rs2200733. Relative excess risk due to interaction (RERI) analysis also revealed significant interaction between rs2106261 and rs2200733 when exposed two copies of risk alleles (RERI=2.87, P<1.00×10-4) or exposed to one additional copy of risk allele (RERI=1.29, P<1.00×10-4). The INTERSNP program identified significant genotypic interaction between rs2106261 and rs2200733 under an additive by additive model (OR=0.85, 95% CI: 0.74-0.97, P=0.02). Mechanistically, PITX2c negatively regulates expression of miR-1, which negatively regulates expression of ZFHX3, resulting in a positive regulation of ZFHX3 by PITX2c; ZFHX3 positively regulates expression of PITX2C, resulting in a cyclic loop of cross-regulation between ZFHX3 and PITX2c. Both ZFHX3 and PITX2c regulate expression of NPPA, TBX5 and NKX2.5. These results suggest that cyclic cross-regulation of gene expression is a molecular basis for gene-gene interactions involved in genetics of complex disease traits.
Indexed as
3' Untranslated RegionsAtrial FibrillationAtrial Natriuretic FactorBase SequenceBinding SitesCase-Control StudiesCaveolin 1Epistasis, GeneticGene ExpressionGenetic Predisposition to DiseaseGenome-Wide Association StudyHomeobox Protein Nkx-2.5Homeobox Protein PITX2Homeodomain ProteinsHumansMicroRNAs3' Untranslated RegionsAtrial Natriuretic FactorCAV1 protein, humanCaveolin 1Homeobox Protein Nkx-2.5Homeobox Protein PITX2Homeodomain ProteinsMicroRNAsMIRN1 microRNA, humanNKX2-5 protein, humanNPPA protein, humanTranscription FactorsZFHX3 protein, human
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