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Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation

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 A...

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Autores principales: Huang, Yufeng, Wang, Chuchu, Yao, Yufeng, Zuo, Xiaoyu, Chen, Shanshan, Xu, Chengqi, Zhang, Hongfu, Lu, Qiulun, Chang, Le, Wang, Fan, Wang, Pengxia, Zhang, Rongfeng, Hu, Zhenkun, Song, Qixue, Yang, Xiaowei, Li, Cong, Li, Sisi, Zhao, Yuanyuan, Yang, Qin, Yin, Dan, Wang, Xiaojing, Si, Wenxia, Li, Xiuchun, Xiong, Xin, Wang, Dan, Huang, Yuan, Luo, Chunyan, Li, Jia, Wang, Jingjing, Chen, Jing, Wang, Longfei, Wang, Li, Han, Meng, Ye, Jian, Chen, Feifei, Liu, Jingqiu, Liu, Ying, Wu, Gang, Yang, Bo, Cheng, Xiang, Liao, Yuhua, Wu, Yanxia, Ke, Tie, Chen, Qiuyun, Tu, Xin, Elston, Robert, Rao, Shaoqi, Yang, Yanzong, Xia, Yunlong, Wang, Qing K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534423/
https://www.ncbi.nlm.nih.gov/pubmed/26267381
http://dx.doi.org/10.1371/journal.pgen.1005393
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author Huang, Yufeng
Wang, Chuchu
Yao, Yufeng
Zuo, Xiaoyu
Chen, Shanshan
Xu, Chengqi
Zhang, Hongfu
Lu, Qiulun
Chang, Le
Wang, Fan
Wang, Pengxia
Zhang, Rongfeng
Hu, Zhenkun
Song, Qixue
Yang, Xiaowei
Li, Cong
Li, Sisi
Zhao, Yuanyuan
Yang, Qin
Yin, Dan
Wang, Xiaojing
Si, Wenxia
Li, Xiuchun
Xiong, Xin
Wang, Dan
Huang, Yuan
Luo, Chunyan
Li, Jia
Wang, Jingjing
Chen, Jing
Wang, Longfei
Wang, Li
Han, Meng
Ye, Jian
Chen, Feifei
Liu, Jingqiu
Liu, Ying
Wu, Gang
Yang, Bo
Cheng, Xiang
Liao, Yuhua
Wu, Yanxia
Ke, Tie
Chen, Qiuyun
Tu, Xin
Elston, Robert
Rao, Shaoqi
Yang, Yanzong
Xia, Yunlong
Wang, Qing K.
author_facet Huang, Yufeng
Wang, Chuchu
Yao, Yufeng
Zuo, Xiaoyu
Chen, Shanshan
Xu, Chengqi
Zhang, Hongfu
Lu, Qiulun
Chang, Le
Wang, Fan
Wang, Pengxia
Zhang, Rongfeng
Hu, Zhenkun
Song, Qixue
Yang, Xiaowei
Li, Cong
Li, Sisi
Zhao, Yuanyuan
Yang, Qin
Yin, Dan
Wang, Xiaojing
Si, Wenxia
Li, Xiuchun
Xiong, Xin
Wang, Dan
Huang, Yuan
Luo, Chunyan
Li, Jia
Wang, Jingjing
Chen, Jing
Wang, Longfei
Wang, Li
Han, Meng
Ye, Jian
Chen, Feifei
Liu, Jingqiu
Liu, Ying
Wu, Gang
Yang, Bo
Cheng, Xiang
Liao, Yuhua
Wu, Yanxia
Ke, Tie
Chen, Qiuyun
Tu, Xin
Elston, Robert
Rao, Shaoqi
Yang, Yanzong
Xia, Yunlong
Wang, Qing K.
author_sort Huang, Yufeng
collection PubMed
description 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.
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spelling pubmed-45344232015-08-24 Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation Huang, Yufeng Wang, Chuchu Yao, Yufeng Zuo, Xiaoyu Chen, Shanshan Xu, Chengqi Zhang, Hongfu Lu, Qiulun Chang, Le Wang, Fan Wang, Pengxia Zhang, Rongfeng Hu, Zhenkun Song, Qixue Yang, Xiaowei Li, Cong Li, Sisi Zhao, Yuanyuan Yang, Qin Yin, Dan Wang, Xiaojing Si, Wenxia Li, Xiuchun Xiong, Xin Wang, Dan Huang, Yuan Luo, Chunyan Li, Jia Wang, Jingjing Chen, Jing Wang, Longfei Wang, Li Han, Meng Ye, Jian Chen, Feifei Liu, Jingqiu Liu, Ying Wu, Gang Yang, Bo Cheng, Xiang Liao, Yuhua Wu, Yanxia Ke, Tie Chen, Qiuyun Tu, Xin Elston, Robert Rao, Shaoqi Yang, Yanzong Xia, Yunlong Wang, Qing K. PLoS Genet Research Article 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. Public Library of Science 2015-08-12 /pmc/articles/PMC4534423/ /pubmed/26267381 http://dx.doi.org/10.1371/journal.pgen.1005393 Text en © 2015 Huang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Huang, Yufeng
Wang, Chuchu
Yao, Yufeng
Zuo, Xiaoyu
Chen, Shanshan
Xu, Chengqi
Zhang, Hongfu
Lu, Qiulun
Chang, Le
Wang, Fan
Wang, Pengxia
Zhang, Rongfeng
Hu, Zhenkun
Song, Qixue
Yang, Xiaowei
Li, Cong
Li, Sisi
Zhao, Yuanyuan
Yang, Qin
Yin, Dan
Wang, Xiaojing
Si, Wenxia
Li, Xiuchun
Xiong, Xin
Wang, Dan
Huang, Yuan
Luo, Chunyan
Li, Jia
Wang, Jingjing
Chen, Jing
Wang, Longfei
Wang, Li
Han, Meng
Ye, Jian
Chen, Feifei
Liu, Jingqiu
Liu, Ying
Wu, Gang
Yang, Bo
Cheng, Xiang
Liao, Yuhua
Wu, Yanxia
Ke, Tie
Chen, Qiuyun
Tu, Xin
Elston, Robert
Rao, Shaoqi
Yang, Yanzong
Xia, Yunlong
Wang, Qing K.
Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation
title Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation
title_full Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation
title_fullStr Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation
title_full_unstemmed Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation
title_short Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation
title_sort molecular basis of gene-gene interaction: cyclic cross-regulation of gene expression and post-gwas gene-gene interaction involved in atrial fibrillation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534423/
https://www.ncbi.nlm.nih.gov/pubmed/26267381
http://dx.doi.org/10.1371/journal.pgen.1005393
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