Study characteristics
After retrieving the database, a total of 545 records [PubMed (n = 146), Web of Science (n=149), EMBASE (n=250)] were obtained. According to the inclusion/exclusion criteria, nineteen articles were included and the detailed flowchart of study selection process was presented in Fig. 1. Twelve studies reported the association between rs505922 and cancer risk [11-13, 17, 23-30] and five studies reported the association between rs657152 and cancer risk [12, 13, 17, 30, 31]. Six studies included nine populations reported the association of cardiocerebrovascular diseases with rs505922 [14, 15, 18-21], and three studies with rs657152 [14, 15, 20]. Detailed characteristics and genotype distribution of included articles for two SNPs were shown in Table 1 and Table 2. In addition, seven additional SNPs which had strong linkage disequilibrium (LD) with rs525922 were reported to be associated with cardiocerebrovascular disease (Table S1) [8, 14, 15, 21, 32-35]. However, the association between these SNPs with cancer risk has not been reported. According to the source of control groups, nine studies were population-based (PB), six studies were hospital-based (HB), and three studies were population and hospital-based(PB/HB) control. For SNP rs505922, ten studies were from Caucasian population[11, 13, 15, 19, 20, 23-26, 29], four studies were from Asian [12, 18, 21, 27] and four studies were from Mixed and African [14, 17, 28, 30]. For the rs657152 polymorphism, there were four studies originating from Caucasian[13, 15, 20, 31], and four studies were from Asian and African or Mixed population [12, 14, 17, 30]. Each study was scored based on the Newcastle-Ottawa Scale (NOS) and detailed study qualities were presented in Table S2 and Table S3.
Meta-analysis of rs505922 polymorphism
Meta-analysis was conducted to estimate the associations between rs505922 and cancer risk (Fig. 2a; Table S4) in 20,820 cancer cases and 27,837 controls. The rs505922 polymorphism was significantly associated with an increased cancers risk in the allele model (OR=1.13, 95%CI=1.05-1.22, P=0.001). Subgroup analysis was conducted based on ethnicity, type of cancer, and source of control. The association between rs505922 and cancer risk was identified in Asian population subgroup (OR=1.27, 95%CI=1.10-1.48, P=0.002), Mixed population subgroup (OR=1.22, 95%CI=1.17-1.27, P<0.001), Pancreatic cancers subgroup (OR=1.23, 95%CI=1.16-1.31, P<0.001), and Hospital based control groups (OR=1.30, 95%CI=1.12-1.51, P=0.003) (Table S5; Fig. S1). However, no significant association was observed in Caucasian population(OR=1.05, 95%CI=0.97-1.13, P=0.232). Sensitivity analyses were conducted by omitting each individual article to measure its specific effect on the pooled ORs (Fig. S2a). Sensitivity analysis plot indicated that no single study significantly affected the combined OR of SNP loci. Because of the heterogeneity of the research, we use the random effect model (allele model: I 2=81.8%) (Table S4). No significant publication bias was observed in any studies of SNPs (Fig. 4a; Table S4). After the applying the trim and fill method, there is no change in the OR value after the combination, also indicating that the original result is stable (Fig. S3).
We also performed a meta-analysis to evaluate the association between rs505922 SNP and cardiocerebrovascular diseases (Fig. 2b; Table S4). The rs505922 SNP was significantly associated with an increased cardiocerebrovascular diseases risk in the allele model (C/T: OR=1.36, 95%CI=1.19-1.57, P<0.001). Subgroup analysis indicated that rs505922 was associated with a significantly higher risk of cardiocerebrovascular diseases in Caucasian population subgroup (OR=1.39, 95%CI=1.19-1.64, P<0.001, allele model), African population subgroup(OR=1.52, 95%CI=1.18-1.96, P=0.001), Hospital based control(OR=1.14, 95%CI=1.05-1.23, P=0.003) and Population based control(OR=1.54, 95%CI=1.18-2.02, P=0.002) (Table S5; Fig. S4). However, no significant association was observed in Asian subgroup (OR=1.21, 95%CI=0.67-2.19, P=0.524) (Table S5; Fig. S4). Sensitivity analysis showed the results of this study were stable (Fig. S2b). There was no significant publication bias among the enrolled studies in Begg’s and Egger’s test (Fig. 4b; Table S4). After applying the trim and fill method, no new literature has been added, indicating that the result is stable (Fig. S5).
Meta-analysis of rs657152 polymorphisms
Five studies reported the association between rs657152 and cancers risk. Our results showed that rs657152 was significantly associated with increased cancers risk in allele model (OR=1.18, 95%CI=1.13-1.23, P<0.001) (Fig. 3a; Table S4). Sensitivity analysis revealed no significant influence on the pooled OR by any individual study (Fig. S6a). We conducted Begg’s and Egger’s tests to assess the publication bias for these studies and no evidence of publication bias was detected among the enrolled studies (Fig. 4c; Table S4). According to the results of trim and fill method, the result was stable (Fig. S7).
We also evaluated the relationship between rs657152 and cardiocerebrovascular diseases. A significant association between rs657152 and cardiocerebrovascular diseases under allele model were observed (OR=1.54, 95%CI=1.24-1.92, P<0.001) (Fig. 3b; Table S4). Sensitivity analysis suggested that there was no significant change in the overall outcomes after removing any of the studies (Fig. S6b). The Begg’s and Egger’s tests also showed that no meaningful publication bias were found (Fig. 4d; Table S4). The result of the trim and fill method proves that the result was stable (Fig. S8).