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

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.

Gene-gene Interaction Analyses for Atrial Fibrillation

“…We also tested the association of rs2106261 at the ZFHX3 locus and rs2200733 at the PITX2 locus with AF, which was recently reported to be associated with AF in a meta-analysis of three Chinese samples (OR = 5.36, P  = 8.0 × 10 −24 )23. The interaction, however, was not significant in any of the 16 studies included in the present paper, or in our meta-analysis (all with P  > 0.05).…”

Evaluation of novel SNPs and haplotypes within the &lt;i&gt;ATBF1&lt;/i&gt; gene and their effects on economically important production traits in cattle

“…Due to the important roles of ATBF1 in regulating myogenesis and adipose tissue development and its close relationship with the HPA axis and JAK-STAT pathways in livestock science (Huang et al, 2015;Jiang et al, 2014;Zhao et al, 2016), ATBF1 was chosen as the candidate gene. In this study, we recovered five SNPs in the bovine ATBF1 gene for the first time.…”

“…In addition, another key gene in the HPA axis pathway, PITX2, has a positive regulation relationship with ATBF1 under the participation of miR-1 (Huang et al, 2015).…”

Myocardial transcription factors in diastolic dysfunction: clues for model systems and disease

“…While several lines of evidence from animal models as well as clinical studies strongly support that PITX2C has a role in susceptibility to atrial fibrillation [94,[109][110][111][112][113][114], the relevance of this TF to LV diastolic dysfunction remained unsuspected and was therefore not tested till recently. LV levels of PITX2C mRNA and protein were first shown to be elevated in the Dox-induced porcine model of HFpEF [97].…”