Significant association of SNP rs2106261 in the ZFHX3 gene with atrial fibrillation in a Chinese Han GeneID population

Abstract

Atrial fibrillation (AF) is the most common cardiac rhythm disorder at the clinical setting and accounts for up to 15% of all strokes. Recent genome-wide association studies (GWAS) identified two single nucleotide polymorphisms (SNPs), rs2106261 and rs7193343 in ZFHX3 (zinc finger homeobox 3 gene) and rs13376333 in KCNN3 (encoding a potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3) that showed significant association with AF in multiple populations of European ancestry. Here, we studied a Chinese Han, GeneID cohort consisting of 650 AF patients and 1,447 non-AF controls to test whether the GWAS findings on ZFHX3/KCNN3 and AF can be expanded to a different ethnic population. No significant association was detected for rs7193343 in ZFHX3 and rs13376333 in KCNN3. However, significant association was identified between rs2106261 in ZFHX3 and AF in the GeneID population for both allelic frequencies (P=0.001 after adjusting for covariates of age, gender, hypertension, coronary artery disease, and diabetes mellitus; OR=1.32), and genotypic frequencies assuming either an additive or recessive model (OR=1.29, P=0.001 and OR=1.77, P =0.00018, respectively). When only lone AF cases were analyzed, the association remained significant (OR=1.50, P=0.001 for allelic association; OR=1.45, P=0.001 for an additive model; OR=2.24, P=0.000043 for a recessive model). Our results indicate that rs2106261 in ZFHX3 confers a significant risk of AF in a Chinese Han population. The study expands the association between ZFHX3 and AF to a non-European ancestry population and provides the first evidence of a cross-race susceptibility of the 16q22 AF locus.

Fig. 1

a Overview of linkage disequilibrium (LD) of the 160 kb region around intron 1 of ZFHX3. The LD structure around SNPs rs7193343 and rs2106261 was derived from the genotyping data of SNPs from the HAPMAP database (http://www.hapmap.org, phase 2, HapMap-CEU). The pairwise correlation between SNPs was measured as D′ and a black diamond without a number refers to D′ = 100. Exons are marked with black boxes. The direction of ZFHX3 transcription is to the left as marked by the arrows. b LD structure between SNPs rs7193343 and rs2106261 predicted based on the HapMap data for the Chinese population (http://www.hapmap.org, phase 2, HapMap-HCB). c LD structure between SNPs rs7193343 and rs2106261 predicted based on the HapMap data for the population of European ancestry (http://www.hapmap.org, phase 2, HapMap-CEU)