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Background  The long non-coding RNA  H19  plays critical roles in cancer occurrence, development, and progression. The present study is for the first time to evaluate the association of genetic variations in the  H19  promoter region with advanced colorectal cancer (CRC) susceptibility, environmental factors, and clinical outcomes.    Methods  16 single-nucleotide polymorphisms (SNPs) were identified in the  H19  gene promoter by DNA sequencing, and 3 SNPs among which including rs4930101, rs11042170, and rs2735970 further expanded samples with 572 advanced CRC patients and 555 healthy controls.    Results  We found that harboring SNP [rs4930101 ( P  = 0.009), rs2735970 ( P  = 0.003), and rs11042170 ( P  = 0.003)] or carrying more than one combined risk genotypes significantly increased the risk for CRC [ P  < 0.0001, adjusted OR (95% CI) 6.48 (2.97–14.15)]. In the correlation analysis with environmental factors, rs2735970 and gender, combined risk genotypes (> 1 vs. ≤ 1) and family history of cancer demonstrated significant interactions. Furthermore, a remarkably worse clinical outcome was found in combined risk genotypes (> 1 vs. ≤ 1), especially in CRC patients with body weight ≥ 61 kg, smoking, and first-degree family history of cancer (Log-rank test:  P  = 0.006,  P  = 0.018, and  P  = 0.013, respectively). More importantly, the multivariate Cox regression analyses further verified that combined risk genotypes > 1 showed a prognostic risk factor for CRC patients with body weight ≥ 61 kg ( P  = 0.002), smoking ( P  = 0.008), and family history of cancer ( P  = 0.006). In addition, MDR analysis consistently revealed that the combination of selected SNPs and nine known risk factors showed a better prediction prognosis and represented the best model to predict advanced CRC prognosis.    Conclusion  3 SNPs of rs4930101, rs11042170, and rs27359703 among 16 identified SNPs of  H19  gene remarkably increased CRC risk. Furthermore, the combined risk genotypes had a significant impact on environmental factors and clinical outcomes in the advanced CRC patients with body weight ≥ 61 kg, ever-smoking, and first-degree family history of cancer. These data suggest that  H19  promoter SNPs, especially these combined SNPs might be more potentially functional biomarkers in the prediction of advanced CRC risk and prognosis.    Electronic supplementary material  The online version of this article (10.1186/s12935-019-0895-x) contains supplementary material, which is available to authorized users.

Functional polymorphisms of the lncRNA H19 promoter region contribute to the cancer risk and clinical outcomes in advanced colorectal cancer