Primitively, a total of 182 articles were collected under the guidance of the retrieve strategy above for further screening. Then, 24 articles containing 52 studies met the inclusive criteria, ranging from Feburary 2008 to July 2019 as for publish date[15-16;21-33]. The flow pathway was shown in Figure 1. [34-40]Distribution of the genotypes in the controls satisfied with HWE. The baseline characteristics of all the studies were extracted and tabulated in Table 1. Asians, Caucasians, Africans and Mixed were involved in these studies. We separated these studies into population-based (PB) and hospital-based (HB) groups to help differentiate between various sources of control. Moreover, the studies collected performed eight genotypic methods altogether, for instance, Illumina, Taqman, Sequenom, etc.
Meanwhile, we calculated the pooled ORs and 95% CIs using five genetic model in order to assess the association between lncRNA H19 ploymorphisms and cancer susceptibility, results of which were tabulated in Table 2. Also, stratification analysis by source of controls along with genotypic method was applied to investigate the heterogeneity of all studies.
rs2839698 G﹥A and cancer susceptibility
Thirteen studies about lncRNA H19 rs2839698 G﹥A ploymorphism and the susceptibility to cancer consisting 7,351 cases and 10,066 controls met the inclusive criteria. The pooled ORs were 1.08 (95% CI: 0.98-1.19) for allele model, 1.08 (95% CI: 0.96-1.23) for dominant model, 1.06 (95% CI: 0.94-1.20) for homozygote model, 1.15 (95% CI: 0.94-1.41) for heterozygote model and 1.12 (95% CI: 0.96-1.31) for recessive model (Figure 2). Despite of no positive results, significant association between rs2839698 G﹥A and cancer susceptibility in population-based controls (allele model: OR=1.17, 95% CI: 1.04-1.31; homozygote model: OR=1.41, 95% CI: 1.04-1.91; recessive model: OR= 1.46, 95% CI: 1.13-1.89) was observed in the stratification analysis by source of control. In addition, no significant results were detected in the subgroup analysis as to the methods of genotyping.
rs217727 G﹥A and cancer susceptibility
Herein, 15 Studies focusing on rs217727 G﹥A polymorphism and cancer susceptibility included 8,164 cases and 10,963 controls. No significant association was indicated through the pooled risk estimation under allele model (OR=1.03, 95% CI=0.94-1.13), dominant model (OR=1.06, 95% CI=0.93-1.22), heterozygous model (OR=1.07, 95% CI=0.92-1.23), homozygous model (OR=1.02, 95% CI=0.85-1.21) and recessive model (OR=0.99, 95% CI=0.84-1.16) (Figure 3). Besides, no positive results were observed in either of the subgroup analysis by source of control and genotypic method.
rs2107425 C﹥T and cancer susceptibility
A total of 11 studies embodying 17,628 controls and 12,292 cases were investigated to LncRNA H19 polymorphic variants rs2107425 C﹥T and the susceptibility to cancer. Analogously, no significant association between rs2107425 C﹥T polymorphism and cancer risk was shown in the meta-analysis according to the pooled ORs of these studies under allele model (OR=0.96, 95% CI=0.89-1.04), dominant model (OR=0.95, 95% CI=0.85-1.06), heterozygous model (OR=0.95, 95% CI=0.84-1.07), homozygous model (OR=0.97, 95% CI=0.83-1.13) and recessive model (OR=0.98, 95% CI=0.87-1.12) (Figure 4). Nevertheless, as to the stratification analysis of genotypic method, the result was significant only in TaqMan (allele model: OR=0.86, 95% CI=0.80-0.94), while no significant results was detected in subgroup of source of control.
rs2735971 A﹥G and cancer susceptibility
The present meta-analysis enrolled 4,393 controls and 3,522 cases from a sum of six studies on rs2735971 A﹥G polymorphism and cancer susceptibility. No significant association was observed among these studies (allele model (OR=0.91, 95% CI=0.75-1.11), dominant model (OR=0.72, 95% CI=0.44-1.17), heterozygous model (OR=0.68, 95% CI=0.41-1.13), homozygous model (OR=0.76, 95% CI=0.45-1.29) and recessive model (OR=0.99, 95% CI=0.89-1.11)) (Figure 5). Additionally, the results of stratified analysis by genotypic method were not positive. By contrast, in subgroup analysis by source of control, feebly positive results were shown in PB control with (dominant model: OR=0.85, 95% CI=0.71-1.00; heterozygous model: OR=083, 95% CI=0.70-0.99).
rs3024270 C﹥G and cancer susceptibility
No significant association existed between rs3024270 mutation and cancer susceptibility as shown by the pooled risks of 8 relevant studies consisting 4,211 cases and 6,014 controls under allele model (OR=1.03, 95% CI=0.98-1.10), dominant model(OR=1.07, 95% CI=0.97-1.18), heterozygous model(OR=1.05, 95% CI=0.95-1.17), homozygous model (OR=1.09, 95% CI=0.97-1.23) and recessive model(OR=1.03, 95% CI=0.94-1.13) (Figure 6). However, stratification analysis by source of control indicated significant association with cancer susceptibility in the PB control group (homozygous model: OR=1.28, 95% CI=1.01-1.61). Additionally, the results of analysis stratified by genotypic method were more significant while using TaqMan than non-TaqMan methods (allele model: OR=1.08, 95% CI=1.01-1.16, dominant model: OR=1.12, 95% CI=1.00-1.26 and homozygous model: OR=1.21, 95% CI=1.05-1.39).
We performed sensitivity analysis by excluding single eligible study sequentially to detect individual study’s influence on the pooled results. According to the results, no single study was found affect the pooled OR in the allele model, suggesting a statistically robust results (Figure 7).
Both Egger’s test and Begg’s funnel plot were utilized in the selected literature. With the symmetrical shapes of funnel plots shown in Figure 8, the absence of publication bias could be testified in the allele model (rs2839698: P=0.222, rs217727: P=0.882, rs2107425: P=0.421, rs2735971: P=0.851 and rs3024270: P=0.322).
Trial sequential analysis results
In this meta-analysis, Figure 9 showed that the information sizes of all the H19 mutations investigated were sufficient except rs2735971 A﹥G polymorphism, indicating that the results about the associations between LncRNA H19 polymorphic variants (rs2839698 G﹥A, rs3024270 C﹥G, rs2107425 C﹥T and rs217727 G﹥A) and the susceptibility to cancer were firm evidence of effect, and the further verification is necessary for the relationship of rs2735971 A﹥G mutation and cancer risk.