Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation.
Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation.
复制标题
基因-基因相互作用的分子基础：参与心房颤动的基因表达的循环交叉调节和 GWAS 后基因-基因相互作用
DOI：
10.1371/journal.pgen.1005393
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发表时间：
2015-08
期刊：
影响因子：
4.5
通讯作者：
Wang QK
中科院分区：
文献类型：
--
作者：
Huang Y;Wang C;Yao Y;Zuo X;Chen S;Xu C;Zhang H;Lu Q;Chang L;Wang F;Wang P;Zhang R;Hu Z;Song Q;Yang X;Li C;Li S;Zhao Y;Yang Q;Yin D;Wang X;Si W;Li X;Xiong X;Wang D;Huang Y;Luo C;Li J;Wang J;Chen J;Wang L;Wang L;Han M;Ye J;Chen F;Liu J;Liu Y;Wu G;Yang B;Cheng X;Liao Y;Wu Y;Ke T;Chen Q;Tu X;Elston R;Rao S;Yang Y;Xia Y;Wang QK
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.
