Association of microRNA biosynthesis genes XPO5 and RAN polymorphisms with cancer susceptibility: Bayesian hierarchical meta-analysis

XPO5/RAN-GTP complex mediates the nuclear transport of pre-miRNAs in the miRNA processing system, its altered expression is indicated to be correlated with cancer risk. Several studies have inspected the association between XPO5 or RAN polymorphisms and the risk of various cancers, but the findings remain controversial. A Bayesian hierarchical meta-analysis was carried out to review and analyze the effect of XPO5 and RAN polymorphisms on cancer risk. The association was estimated by calculating the logarithm of odds ratio (Log OR) and 95% credible interval (95% CrI). The expression quantitative trait loci (eQTL) analysis was used for in silico functional validation of the identified significant susceptibility loci. Consequently, 38 case-control studies (from 27 citations) with 27,459 cancer cases and 25,151controls were included in the meta-analysis of the five most prevalent SNPs (rs11077 A/C, rs2257082 G/A, rs3803012 A/G, rs14035 C/T, rs3809142 C/T). In the XPO5 gene rs11077 SNP, the minor C allele significantly increased the risk of cancer (Log OR = 0.120, 95% CrI = 0.013, 0.241), and a strong association between rs11077 SNP and cancer risk was also found in the dominant model (CC + AC vs. AA: Log OR = 0.132, 95% CrI = 0.009, 0.275). In addition, the minor GG genotype allele of the RAN gene rs3803012 SNP significantly increased the cancer risk (Log OR = 0.707, 95% CrI = 0.059, 1.385). Statistically significant associations between rs3803012 SNP and cancer risk were also observed in the recessive model (GG vs. AG + AA: Log OR = 0.708, 95% CrI = 0.059, 1.359). Furthermore, the eQTL analysis revealed that rs11077 SNP was significantly correlated with XPO5 mRNA expression, which provided additional biological basis for the observed positive association. Our results suggest that XPO5 rs11077 may be a possible functional susceptibility locus for cancer risk.