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


Gene-gene interaction is assumed to be critical to the pathogenesis of human disease, but its contribution to human disease phenotype needs definitive documentation. Moreover, the underlying molecular mechanism for gene-gene interaction is unknown. Here we use atrial fibrillation (AF) as a model to demonstrate that gene-gene interaction plays an important role in disease pathogenesis. Only three of the ten AF loci identified by GWAS in European ancestry populations, including PITX2c, ZFHX3, and CAV1, were replicated in the Chinese population and thus selected for gene-gene interaction studies. We show that the PITX2c locus interacts with the ZHFX3 locus to increase the risk of AF. Because gene-gene interaction can generate synergistic effect that markedly increases risk of AF, we conclude that gene-gene interaction accounts for a significant portion of heritability of AF. Mechanistically, PITX2c positively regulates ZHFX3 via miR-1 and ZHFX3 positively regulates PITX2c, which generates a loop of cross-regulation of the two genes. Our study suggests that cyclic cross-regulation of gene expression is a molecular basis for gene-gene interaction involved in disease phenotype.


Vyšlo v časopise: Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation. PLoS Genet 11(8): e32767. doi:10.1371/journal.pgen.1005393
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1005393

Souhrn

Gene-gene interaction is assumed to be critical to the pathogenesis of human disease, but its contribution to human disease phenotype needs definitive documentation. Moreover, the underlying molecular mechanism for gene-gene interaction is unknown. Here we use atrial fibrillation (AF) as a model to demonstrate that gene-gene interaction plays an important role in disease pathogenesis. Only three of the ten AF loci identified by GWAS in European ancestry populations, including PITX2c, ZFHX3, and CAV1, were replicated in the Chinese population and thus selected for gene-gene interaction studies. We show that the PITX2c locus interacts with the ZHFX3 locus to increase the risk of AF. Because gene-gene interaction can generate synergistic effect that markedly increases risk of AF, we conclude that gene-gene interaction accounts for a significant portion of heritability of AF. Mechanistically, PITX2c positively regulates ZHFX3 via miR-1 and ZHFX3 positively regulates PITX2c, which generates a loop of cross-regulation of the two genes. Our study suggests that cyclic cross-regulation of gene expression is a molecular basis for gene-gene interaction involved in disease phenotype.


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