Eligible studies
In total, nighty-six articles were collected from the PubMed, Embase and Wanfang databases. 89 articles were excluded (25-irrelated articles, 4-systematic/Meta-analysis, 1-only case group, 23-supplement, 30-duplication and 6-no original numbers for case/control groups) (Figure 1). Finally, seven articles were identified in current analysis, including 3,674 cases and 8,990 healthy controls related to ZFHX3 rs2106261 polymorphism and 1045 cases and 1407 controls for PRRX1 rs3903239 polymorphism. The characteristics of each included study are listed in Table 1. In addition, the Minor Allele Frequency (MAF) reported from the five main worldwide populations in the 1000 Genomes Browser are checked (https://www.ncbi.nlm.nih.gov/snp/): African; European; East Asian; American and South Asian (Figure 2), which was similar with the average level in our current case and control groups.
Meta-analysis
ZFHX3 rs2106261 polymorphism and AF risk
In the overall analysis, significantly increased associations was observed in five genetic models in Asians: in the allelic contrast (OR[95% CI] = 1.39[1.31-1.47], Pheterogeneity = 0.117, P < 0.001, Figure 3A), the heterozygote comparison (OR[95% CI] =1.37[1.18-1.59], Pheterogeneity = 0.007, P < 0.001, Figure 3B), AA vs. CC (OR[95% CI] = 1.96[1.73-2.21], Pheterogeneity = 0.317, P < 0.001, Figure 3C), the dominant model (OR [95% CI] = 1.49[1.30-1.70], Pheterogeneity = 0.011, P < 0.001, Figure 3D) and AA vs. AC +CC (OR[95% CI] = 1.70[1.52-1.90], Pheterogeneity = 0.643, P < 0.001, Figure 3E) (Table 2).
In the subgroup analysis by source of control, ZFHX3 rs2106261 A-allele or AA genotype acted as an risk factor in both HB and PB subgroups: HB (such as: A-allele versus C-allele: OR[95% CI] = 1.51[1.38-1.64], P(heterogeneity) = 0.302, P < 0.001; AC versus CC: OR[95% CI] = 1.57[1.38-1.79], P(heterogeneity) = 0.156, P < 0.001) and PB (such as: A-allele versus C-allele: OR[95% CI] = 1.31[1.21-1.41], P(heterogeneity) = 0.321, P < 0.001; AC versus CC: OR[95% CI] = 1.17[1.04-1.30], P(heterogeneity) = 0.584, P = 0.007) (Figure 3A,B, Table 2).
To detect whether the association were existed between genotype methods and ZFHX3 rs2106261 polymorphism, we carried out the next step. Several positive results were found in TaqMan [in the allelic contrast (OR = 1.55, 95% CI = 1.33-1.80, P = 0.740 for heterogeneity, P < 0.001 for significant), the heterozygote comparison (OR =1.82, 95% CI = 1.46-2.27, P = 0.668 for heterogeneity, P < 0.001), AA vs. CC (OR = 2.06, 95% CI = 1.48-2.86, Pheterogeneity = 0.884, P < 0.001 for significant), the dominant model (OR[95% CI] = 1.87[1.52-2.30], Pheterogeneity = 0.674, P < 0.001) and AA vs. AC +CC (OR[95% CI] = 1.51[1.11-2.06], Pheterogeneity = 1.000, P < 0.001), High-Resolution Melt (HRM) [in the allelic contrast (OR = 1.31, 95% CI = 1.21-1.41, Pheterogeneity = 0.647, P < 0.001), the heterozygote comparison (OR =1.17, 95% CI = 1.04-1.30, P = 0.584 for heterogeneity, P = 0.007 for significant), AA vs. CC (OR = 1.81, 95% CI = 1.54-2.12, Pheterogeneity = 0.417, P < 0.001), the dominant model (OR = 1.29, 95% CI = 1.16-1.43, P = 0.655 for heterogeneity, P < 0.001) and AA vs. AC +CC (OR = 1.68, 95% CI = 1.45-1.94, Pheterogeneity = 0.384, P < 0.001 for significant) and Others (data not shown) (Figure 4, Table 2).
PRRX1 rs3903239 polymorphism and AF risk
Decreased associations were found in heterozygote comparison (OR[95% CI] = 0.83[0.77-0.99], Pheterogeneity = 0.522, P = 0.036, Figure 5A, Table 2) and dominant model (OR[95% CI] = 0.79[0.67-0.94], P = 0.137 for heterogeneity,, P = 0.006, Figure 5B, Table 2).
Sensitivity analysis and publication bias
A Begg funnel chart and Egger test were performed to assess publication bias. The results did not show any evidence of publication bias (for example: A-allele versus G-allele, t = 1.46, P = 0.205 [Egger test]; z = 1.2, P = 0.23[Begg test] for ZFHX3 rs2106261, Figure 6; C-allele versus T-allele, t = 0.11, P = 0.933 [Egger test]; z = 0.0, P = 1.00 [Begg test] for PRRX1 rs3903239, Figure 7, Table 3). A sensitivity analysis was performed to assess the impact of each individual study on the combined OR by removing individual studies one by one. The results suggested that no separate study significantly affected the overall OR for ZFHX3 rs2106261 (Figure 8).
Network of gene-gene interaction of ZFHX3 and PRRX1 gene, respectively.
The network of potential gene-gene interaction for ZFHX3 and PRRX1 genes was analyzed by String online webpage (http://string-db.org/) [33] (Figure 9). Each gene was shown ten significant related genes in the web of relationships.