Abstract
Based on 540 hepatocellular carcinoma patients and 540 age- and gender-matched controls, we tested the hypothesis that high mobility group protein box1 (HMGB1) and the receptor for advanced glycation end products (RAGE) genes are two potential candidate susceptibility genes for hepatocellular carcinoma in a multicenter hospital-based case-control analysis. The genotypes of seven widely-studied polymorphisms were determined, and their distributions respected the Hardy-Weinberg equilibrium. The mutant alleles of two polymorphisms, rs1045411 in HMGB1 gene and rs2070600 in RAGE gene, had significantly higher frequencies in patients than in controls (P < 0.001), with the power to detect this significance of being over 99.9%. Moreover, the above two polymorphisms increased the risk of developing hepatocellular carcinoma significantly, particularly for rs2070600 under the additive (odds ratio [OR] = 1.77; 95% confidence interval [CI]: 1.34-2.32; P < 0.001) and dominant (OR = 1.75; 95% CI: 1.23-2.50; P = 0.002) models after adjusting for body mass index, smoking and drinking. Haplotype analysis showed that the T-C-T haplotype (rs1045411-rs2249825-rs1415125) in HMGB1 gene was associated with a 2.47-fold (95% CI: 1.41-4.34; P = 0.002) increased risk of hepatocellular carcinoma compared with the commonest C-C-T haplotype after adjustment. In RAGE gene, the T-T-A-G (rs1800625-rs1800624-rs2070600-rs184003) (adjusted OR; 95% CI; P: 1.75; 1.02-3.03; 0.045) and T-T-A-T (adjusted OR; 95% CI; P: 1.95; 1.01-3.76; 0.048) haplotypes were associated with a marginally increased risk of hepatocellular carcinoma compared with the commonest T-T-G-G haplotype. In summary, we identified two risk-associated polymorphisms (rs1045411 and rs2070600), and more importantly a joint impact of seven polymorphisms from the HMGB1/RAGE axis in susceptibility to hepatocellular carcinoma.
Highlights
The importance of the ligand-receptor axis involving high mobility group protein box1 (HMGB1) and the receptor for advanced glycation end products (RAGE) in inflammation and tumorigenesis has been increasingly recognized by many experimental and clinical investigators [1,2,3,4]
Haplotype analysis showed that the T-C-T haplotype in HMGB1 gene was associated with a 2.47-fold increased risk of hepatocellular carcinoma compared with the commonest C-C-T haplotype after adjustment
In RAGE gene, the commonest T-T-G-G haplotype was frequently seen in controls compared with patients, and relative to this haplotype, T-T-A-G (OR; 95% CI; P: 1.75; 1.02-3.03; 0.045) and T-T-A-T (OR; 95% CI; P: 1.95; 1.01-3.76; 0.048) haplotypes were associated with a marginally increased risk of hepatocellular carcinoma after adjusting for confounders mentioned above, with the study power of 28.0% and 71.9%, respectively. In this multicenter matched case-control study, we set out to examine the hypothesis that HMGB1 and RAGE genes are two potential candidate susceptibility genes for hepatocellular carcinoma
Summary
The importance of the ligand-receptor axis involving high mobility group protein box (HMGB1) and the receptor for advanced glycation end products (RAGE) in inflammation and tumorigenesis has been increasingly recognized by many experimental and clinical investigators [1,2,3,4]. HMGB1 is a nuclear DNAbinding factor that exerts an important regulatory role in chromatin architecture and transcriptional regulation [5]. The binding of HMGB1 to RAGE can stimulate the expression of Ras, PI3K, and Rho, which are major www.impactjournals.com/oncotarget Characteristics Patients Controls P* Age (years) 51.5 (6.7) 50.4 (6.8) Male gender BMI (kg/m2) 25.4 ± 2.2
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