In this study, we have developed and validated a novel human left atrial cellular model (TPA) based on the ten Tusscher-Panfilov ventricular cell model to systematically investigate how electrical remodeling induced by TBX5/PITX2 insufficiency leads to AF.
Among the 8 AF risk SNPs genotyped, only rs10033464 SNP at chromosome (chr) 4q25 (near PITX2) was significantly associated with development of AF after multiple risk factor adjustment and multiple testing (adj. odds ratio [OR] 2.27, 95% confidence interval [CI] 1.31-3.94; P = 3.3 x 10-3).
Polymorphisms in PITX2 (rs2200733) and IL6 (rs1800795) are associated with postoperative atrial fibrillation in adults but have not been studied in CHD.
Loss of the paired-like homeodomain transcription factor 2 (<i>Pitx2</i>) in cardiomyocytes predisposes mice to atrial fibrillation and compromises neonatal regenerative capacity.
Genome-wide association analysis of all-cause HF identified several suggestive loci ( P<1×10<sup>-6</sup>), the majority linked to upstream HF risk factors, ie, coronary artery disease ( CDKN2B-AS1 and MAP3K7CL) and atrial fibrillation ( PITX2).
To potentially model aspects of AF and unravel PITX2-regulated downstream genes for drug target discovery, we here report the generation of integration-free PITX2-deficient hiPS cell lines.
Pitx2 deficiency results in electrical and structural remodelling, and impaired repair of the heart in murine models, all of which may influence AF through divergent mechanisms.
Whereas large body of evidences has been provided in recent years on PITX2 downstream signaling pathways, scarce information is available on upstream pathways influencing PITX2 in the context of AF.
In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10<sup>-5</sup>).
TBX5/PITX2 interplay provides tight control of atrial rhythm effector gene expression, and perturbation of the co-regulated network caused AF susceptibility.
Genome-wide association studies (GWAS) have identified common variants in nine genomic regions associated with AF (KCNN3, PRRX1, PITX2, WNT8A, CAV1, C9orf3, SYNE2, HCN4 and ZFHX3 genes); however, the genetic variability of these risk variants does not explain the entire genetic susceptibility to AF.
Our data suggest that de-regulation of both PITX2 and ENPEP could contribute to an increased risk of atrial fibrillation in carriers of disease-associated variants, and show the challenges that we face in the functional analysis of genome-wide disease associations.
In dementia patients, there was an association between the PITX2 loci and AF (rs2634073: odds ratio [OR] = 2.11; P = 0.025 and rs2200733: OR = 2.27; P = 0.029).
Common single nucleotide polymorphisms (SNPs) at chromosomes 4q25 (rs2200733, rs10033464 near PITX2), 1q21 (rs13376333 in KCNN3), and 16q22 (rs7193343 in ZFHX3) have consistently been associated with the risk of atrial fibrillation (AF).