After the age of 60 years, patients with LQT2 had significantly lower risk of AF compared with genotype-negative controls (hazard ratio=0.07; 95% CI, 0.01-0.53, <i>P</i>=0.011).
Various genes involved in Ca<sup>2+</sup> handling or gap junction formation ( Ryr2, Jph2, Gja5), potassium channels ( Kcnh2, Kcnk3), and genes implicated in atrial fibrillation ( Tbx5) were part of this ETV1-driven gene regulatory network.
A benign variety of the disease has been observed in children with atrial fibrillation and a KCNH2-V141M mutation, and recently a mutation in the cardiac Cl/HCO<sub>3</sub> exchanger AE3 was found to cause SQTS.
Together with the findings that caveolin-1 interacts with potassium channels Kir2.1, KCNH2, and HCN4 and sodium channels Nav1.5 and Nav1.8, CAV1 becomes a strong candidate susceptibility gene for AF across different ethnic populations.
Using a linear regression model and adapting a resampling inference, a decrease in longitudinal QTc variance was found to associate with SNPs near KCNH2 (rs10240738) and KCNJ2 (rs8079702) when adjusted for patient age, gender, AF type, and average QTc.
In overall random-effects meta-analyses, association with AF was observed for both SNPs on chromosomes 4q25 [odds ratio (OR), 1.67; 95% CI, 1.50-1.86, P=2×10(-21)] and 16q22 (OR, 1.21; 95% CI, 1.13-1.29, P=1×10(-8)) from genome-wide studies, but not the SNP in KCNH2 from candidate gene studies (P=0.15).
In a pair-matched, hospital-based case control study (297 vs 297) conducted in Chinese Hans, we investigated 4 tagging single nucleotide polymorphisms (tSNPs), rs1805120, rs1036145, rs3807375, and rs2968857 in the KCNH2 gene, and determined their association with AF acquired from structural heart diseases.
Rs13376333 on chromosome 1q21 (in KCNN3), rs7193343 and rs2106261 on chromosome 16q22 (in ZFHX3) were not associated with AF recurrence in our meta-analysis.
Atrial rhythm instability caused by Tbx5 haploinsufficiency was rescued by a decreased dose of phospholamban, a sarco/endoplasmic reticulum Ca2+-ATPase inhibitor, consistent with a role for decreased sarcoplasmic reticulum calcium flux in Tbx5-dependent AF susceptibility.