Atrial fibrillation (AF) represents the most serious sustained arrhythmia in the process of clinical diagnosis and treatments. It is the feature of uncoordinated atrial activation. Some studies shown that AF was a important factor with a lifetime risk of one in four for men and women 40 years of age and older [27]. Currently, a number of studies showed that AF was in the relationship of SNPs in genes [13, 28, 29]. A SNP, rs7193343, had been investigated widely. Although several studies demonstrated that rs7193343 polymorphism was associated with occurrence of AF, the results were still in controversy. We, therefore, conducted the present meta-analysis to evaluate the relationship of rs7193343 polymorphism and susceptibility of AF. Thus, we aim to provide objective evidence in the investigation of rs7193343 polymorphism in patients with AF, based on the current published studies.

Recently, a growing body of researches provided the relationship of a variant in the ZFHX3 gene on chromosome 16q22, rs7193343-T and AF in multiple population of different ancestry. However, their conclusions were not consistent. The distribution of genotype of rs7193343 polymorphism in ZFHX3 gene differed significantly among populations. Gudbjartsson et al. [14] expanded a genome-wide association study (GWAS) on atrial fibrillation, they previously identified risk variant on 16q22 rs7193343 associated significantly with AF in samples from Iceland, Norway and US, they also illustrated that the association of SNPs rs7193343-T with AF in Chinese population from Hong Kong, but the result was not significant in this cohort. Furthermore, they found that the T allele of rs7193343 is obviously much more frequent in Chinese descent than the samples of European population. Soon afterwards, the study of Cong L et. al [16] provided the first evidence of a cross-race susceptibility of the 16q22 AF locus in a Chinese Han population, and expanded the association between ZFHX3 and AF to a non-European ancestry population. They carried out a large-scale case-control association study, and identified that ZFHX3 SNP rs7193343 was not associated with AF in the Chinese Han population. Kiliszek et al. [15] identified SNP rs7193343 polymorphism correlated significantly with AF in Polish patients, and confirmed rs7193343 on chromosome 16q22 that it was an independent marker of AF. Although another study evaluated genomic markers which can predict timing of AF recurrence in patients undergoing elective direct current cardioversion, it did not confirm that rs7193343 has association with early AF recurrence [24].

The present study demonstrated that there was statistically significant in the association between T-allele frequency of rs7193343 and AF in overall population. Interestingly, subgroup analysis was performed according to the ethnicity, showing significant association between T-allele frequency of rs7193343 and AF in Caucasian population but not in Asian population. Although a previous meta-analysis was conducted recently with positive results [25], no subgroup analysis was performed based on the ethnicity. The heterogeneity originated from ethnicity was of great importance in the pooled results. Thus, it was imperative to update the previous meta-analysis in accordance with ethnicity of individual study. The pooled result based on one kind of ethnicity may be more stable. Although the pooled results in overall population of the present study was consistent with the previous one, there was no statistically significant difference in Asian population. The subgroup analysis is the strengthen of the present meta-analysis.

Rs7193343 is an intronic SNP located in the zinc finger homeobox 3 (ZFHX3) gene (chromosome 16q22) [14]. The variant is also called AT motif-binding factor 1 (ATBF1). The same variant was associated with Kawasaki disease, an inflammatory vasculitis predominantly seen in young children. The gene encodes a transcription factor named Atbf1 that was first described as an enhancer of human a-fetoprotein (AFP) gene expression in the liver [30]. This gene regulates neuronal and muscle differentiation and is a tumor suppressor gene in several types of cancer [31]. ZFHX3 is expressed in various tissues, including heart, liver, lung, kidney, pituitary gland and brain. Although it is expressed in mouse heart [32], its function in heart tissue is unknown. Atbf1 is required for early transcriptional activation of the gene POU class 1 homeobox 1 (POU1F1) that regulates pituitary cell differentiation and hormone expression in mammals [33]. POU1F1 interacts with the paired-like homeodomain transcription factor 2 (PITX2) to facilitate DNA binding and transcriptional activity, which is of interest because the previously identified AF variants on chromosome 4q25 are located close to PITX2, a gene critical for heart development [34]. Therefore, we speculate there is an association between rs7193343 and expression of ZFHX3 in heart tissue. The above mentioned may be the mechanism of the association between ZFHX3 rs7193343 polymorphism and the risk of AF.

The following potential factors may be account for the different pooled results between the above two ethnical group: (1) inconsistence in genetic background [35], (2) different habits in individual ethnicity [36], (3) environmental factors leading to different susceptibility of AF [37]. Furthermore, we also speculate that the reason why the statistical difference was not significant in Asian population after subgroup analysis may be the limited sample size in this population. Therefore, more studies with large sample size are required to conduct further analysis, especially in Asian population.

Although the results of test for heterogeneity were not significant for subgroup population, heterogeneity cannot be completely resolved. The heterogeneity of included studies includes the following: quality of included studies, gender proportion, age, classification of AF, different genetic background, environmental factors, sampling criteria and cultural difference. The heterogeneity of genetic effects between individual studies may also be caused by the existence of gene-environmental or genetic interaction. In spite of only ten comparisons included, the pooled results may have clinical significance according to the current evidence. Although no publication bias was found in the present study, it is also important to bear in mind that publication bias may exist, since the negative results are less likely to be published. Accordingly, while the results of this meta-analysis should be considered appropriate, the above methodological defects should be considered when interpreting the findings. The present study could provide objective evidence by using genetic meta-analysis approach.

The primary limitations of this updated meta-analysis include the following: (1) the statistical efficacy could be improved by including more studies; (2) Some non-English publications not being included in this study may have caused important studies to be overlooked and publication bias from significant conclusions being more easily published; (3) The genotyping data of SNPs rs7193343 were insufficient, so we were unable to conduct meta-analysis based on the limited studies data; (4) the combined analysis of the results may be affected by the impact of clinical heterogeneity, including the general condition of the cases, habits, medical history, medication compliance and other factors.