| Hepatocellular carcinoma (HCC) is a complex disease, both genetic factors and environmental factors play important roles in the development of this disease. In order to explore the association of genetic variations of two genetic factors (survivin and COX-2) with HCC, as well as the gene-gene and gene-inviroment interactions in East China Han population, a case-control study design was adopted, with the aid of some molecular biologic techniques, such as polymorphism chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Futhermore, we evaluated the diagnostic value of associated genetic variations on HCC. The results are as follows:PartⅠThe association of single-locus based genetic variations with HCC1. For locus rs8073069, rs9904341 and rs1042489 in survivin gene, neither genotypic or allelic frequencies were significantly different between HCC patients and controls (all P values were greater than 0.05). No significant association was found between the three polymorphisms and HCC in multiple logistic regression.2. For locus rs689466 in COX-2 gene, theχ2 test showed that genotypic frequencies in case groups were significantly different from controls in the recessive genetic model (χ2=5.456, P=0.019). Individuals with genotype GG had a lower onset risk for HCC compared with those having genotype AA or AG, with OR=0.55 (95%CI:0.34～0.91). Allelic frequencies were significantly different within groups (χ2=4.642,P=0.031), and there was a lower proportion of allele G in cases (42.13%) than that in controls (50%), which implies that G allele of rs689466 may reduce the risk for HCC, with OR=0.73 (95%CI: 0.55～0.97).3. For locus rs20417 in COX-2 gene, theχ2 test showed that genotypic frequencies in HCC case groups were significantly different from controls in the recessive genetic model (x2=5.441, P=0.020). Individuals with genotype GG had a lower onset risk for HCC compared with those having genotype CC or CG, with OR=0.45 (95%CI:0.23-0.89). Allelic frequencies were significantly different within groups (x2=5.134, P=0.023), and there was a lower proportion of allele G in HCC patients (92.70%) than that in controls (96.43%), which implies that G allele of rs20417 may reduce the risk for HCC, with OR=0.47 (95%CI:0.24～0.92).4. Multiple logistic regression reviewed that rs689466A/G polymorphism correlated with HCC in the additive and recessive genetic model after adjustment of the factors (age, gender, drinking, et al). Individuals with genotype GG had a lower onset risk for HCC in contrast to individuals having genotype AA or AA/AG, with OR=0.54 (95%CI:0.30～0.97) and 0.57 (95%CI:0.34～0.94) respectively. Multiple logistic regression also showed that rs20417C/G polymorphism correlated with HCC in the recessive genetic model after adjustment of these factors. Individuals with genotype GG had a lower onset risk for HCC in contrast to individuals having genotype CC/CG, with OR=0.43 (95%CI:0.22～0.86).PartⅡThe association of haplotype with HCC1. It was found that there were significant linkage disequilibrium between locus of rs8073069 and rs9904341, rs8073069 and rs 1042489, rs 1042489 and rs9904341 in survivin gene (x2 was 148.267,216.739 and 8.796 respectively, all P values were less than 0.05), with D'being 0.916,0.945 and 0.189; r2 being 0.288,0.425 and 0.026 respectively. For COX-2 gene, rs689466 and rs20417 was also in linkage disequilibrium (x2=11.961, P<0.05), with D'being 0.717 and r2 being 0.025.2. The association of the haplotypes composed of the alleles of rs8073069C/G, rs9904341C/G and rs1042489C/T in survivin gene with HCC were explored under different genetic models using HAPSTAT 3.1 software. The ressecive genetic model was the optimal model. With no G-C-T haplotype as reference, it was found that the haplotype of G-C-T from the three loci was associated with a lower risk for HCC under the recessive genetic model, with OR=0.46,95%CI: 0.24-0.90 (P=0.023).3. The association of the haplotypes composed of the alleles of rs689466 and rs20417 in COX-2 gene with HCC were explored under different genetic models using HAPSTAT 3.1 software. The additive genetic model was the optimal model. With no G-G haplotype as reference, it was found that the haplotype of G-G from the two loci was associated with a lower risk for HCC under the additive genetic model, with OR=0.45,95%CI:0.22-0.90 (P=0.024).4. The interactions between haplotype and haplotype, as well as haplotype and invironmental factors were explored using the software of HAPSTAT 3.1. No significant interaction was found under different genetic models.PartⅢThe study of interactions between gene-gene and gene-invironment for HCC1. For case-only data, we performed log-linear model analysis. Under the additive genetic model, there were interactions between the genotype GG on rs8073069 and AG on rs689466((αβ)XY=-2.240, P=0.035), CG on rs8073069 and AG on rs689466 ((αβ)XY=-2.175, P=0.044), as well as GG on rs8073069 and a history of hepatitis B ((αβ)XZ=-1.145, P=0.040). Under the dominant genetic model, there were interactions between the genotype CG or GG on rs8073069 and AG or GG on rs689466 ((αβ)XY=-2.124, P=0.042). Under the ressecive genetic model, there was interaction between the genotype GG on rs8073069 and a history of hepatitis B ((αγ)XZ=-0.608, P=0.049).2. For case and control data, logistic regression was fitted for rs8073069 in survivin gene and rs689466 in COX-2 gene. Under the additive genetic model, there were interactions between the genotype CG on rs8073069 and AG on rs689466 (β=-3.679, P=0.005), CG on rs8073069 and GG on rs689466 (β=-3.359, P=0.010), as well as GG on rs8073069 and AG on rs689466 (β=-3.132, P=0.030). Under the dominant genetic model, there were interactions between the genotype CG or GG on rs8073069 and AG or GG on rs689466 (β=-3.166, P=0.009). However, no significant interaction existed under the ressecive genetic model. Moreover, the dominant genetic model was the optimal one.3. For case and control data, logistic regression was fitted for rs1042489 in survivin gene and rs689466 in COX-2 gene. The results showed that except for the interaction existed between the genotype TT on rs1042489 and AG on rs689466 (β=-1.794, P=0.036) under the additive genetic model, no statistic significance was found, while the ressecive genetic model was the optimal model.PartⅣThe evaluation of the diagnostic value of genetic variations on early HCC1. For rs689466 in COX-2 gene, sensitivity=54.49%, specialty=58.67%, Youden's index=13.16%. The arear under the ROC curve (AUC) was 0.583, with its 95%CI: 0.525～0.641. As compared with 0.5, the difference was statistically significant (P=0.005).2. For rs20417 in COX-2 gene, sensitivity=21.91%, specialty=88.78%, Youden's index=10.69%. The AUC was 0.557, with its 95%CI:0.498-0.615. As compared with 0.5, the difference was not statistically significant (P=0.058).3. For the combination of rs689466 and rs20417 in COX-2 gene, sensitivity=42.13%, specialty=71.43%, Youden's index=13.56%. The AUC was 0.605, with its 95%CI: 0.548～0.662. As compared with 0.5 or rs20417, the difference was statistically significant (P<0.001 and=0.019, respectively); while not different from rs689466 (P=0.159).4. For the combination of rs689466, rs20417 and environmental factors, sensitivity=79.21%, specialty=93.88%, Youden's index=73.09%. The AUC was 0.908, with its 95%CI:0.876～0.941. As compared with 0.5, rs689466, rs20417, or the combination of rs689466 and rs20417, the difference was statistically significant (P<0.001). |
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