CHAPTER II-1
INTEGRIN ALPHA V POLYMORPHISMS IN KOREAN POPULATION ARE ASSOCIATED WITH SUSCEPTIBILITY TO CHRONIC HEPATITIS B AND HEPATOCELLULAR CARCINOMA
Background/Aims
Integrins are cell surface receptors for extracellular matrix (ECM) proteins that initiate signaling pathways that modulate proliferation, survival, invasion, or metastasis. Consequently, integrins are potential targets for the treatment of cancer. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in integrin αV(ITGAV)in a Korean population were associated with chronic hepatitis B virus (HBV) infection (CHB) and HBV-infected hepatocellular carcinoma (HCC).
Methods
Thirteen ITGAV SNPs in 111 cases of chronic HBV infection, 86 cases of HBV-infected HCC, and 107 cases of HBV clearance were genotyped by using Illumina’s Sentrix Array Matrics (SAM) chip.
Results
The ITGAV intron SNPs rs9333289 and rs11685758, the 3´ un-translated region SNP rs1839123, and haplotype 3 (T-T-A) were associated with enhanced susceptibility to HBV-infected HCC (OR=1.75∼2.42; p=0.02∼0.05), while the intron SNP rs2290083 was associated with both chronic infection and HBV-infected HCC (OR=1.73∼2.01; p=0.01∼0.04). In addition, both rs2290083 and ht1 [C-C-G] were associated with the age at which chronic infection occurred, as determined by Cox relative hazard analysis (RH=1.39∼1.62, P=0.04∼0.01)
Conclusion
ITGAV SNPs and haplotype may be genetic factors to increase the susceptibility of Koreans to chronic HBV infection and HBV-infected HCC.
CHAPTER II-2
GENETIC ASSOCIATION BETWEEN COLLAGEN TYPE III ALPHA I AND CHRONIC HEPAPTITIS B AND LIVER CIRRHOSIS IN KOREAN
Collagen type III alpha 1 (COL3A1) is one of the extracelluar matrix (ECM) proteins that the expression of COL3A1 is closely related to chronic liver diseases. Here, we investigated whether single nucleotide polymorphisms (SNPs) of COL3A1 confer genetic susceptibility to the persistence of hepatitis B virus (HBV), liver cirrhosis (LC), and hepatocellular carcinoma (HCC).
A total of 399 Korean people, 111 patients with chronic hepatitis B (CHB), 95 patients with LC, 86 patients with HCC, and 107 HBV clearances from HBV infection, were genotyped for 16 SNPs of the COL3A1 gene.
The SNP of rs3106796 A allele was highly associated with the CHB (OR=1.62; p=0.01), LC (OR=1.67; p=0.01), and HCC (OR=1.59; p=0.03) in allele model. There were six polymorphic SNPs that could be divided into two linkage disequilibrium (LD) blocks. The haplotype pattern of the Korean control seems to be similar to the patterns displayed in the Japanese, Chinese, and Caucasian populations sampled in the International HapMap project. This SNP belongs to the second LD block with two other distal polymorphic SNPs (rs1800255 and rs2271683). Haplotype 3 (A-G-A) of the LD block 2 was significantly associated with CHB (OR=2.23; p=0.02), LC (OR=2.24; p=0.03), and HCC (OR=2.27; p=0.03). Moreover, diplotype analysis showed increased relative risk for CHB and LC in the two diplotypes, dt3 (A-G-A/G-G-A; OR=4.05, p=0.01) and dt6 (A-A-A/A-G-A; OR=7.42, p=0.01 and OR=5.84, p=0.023, respectively) against dt1 (G-G-A/G-G-A), the most common diplotype in both Korean groups. In vitro reporter gene assays showed that the constructs containing the “G” allele of rs3106796 appear to exert lower transcriptional activity of COL3A1 than the “A” allele, depending on the promoter types.
COL3A1 SNPs, haplotypes, and diplotypes may be genetic factors for increased susceptibility to chronic HBV infection, cirrhosis, and HBVinfected HCC.
CHAPTER II-3
FUNCTIONAL GENETIC VARIATIONS OF CARBONIC ANHYDRASE II IN A KOREAN POPULATION ARE ASSOCIATIED WITH INCREASED RISK OF HEPATOCELLULAR CARCINOMA
Development of hepatocellular carcinoma (HCC) is accompanied by complex changes in the expression levels of various genes. Interestingly, several reports are showed that decreased expression of carbonic anhydrase (CA) II is associated with HCC. These are proposed to result from reduced revels of a transcription factors or loss of alleles. In this study, we investigated whether the naturally occurred sequence variations in the CAII influences impact of HCC in a Korean population.
The case-control study consisted of a total 399 subject including 111 hepatitis B viruses (HBV) chronic infection (CHB), 95 HBV infected liver cirrhosis (LC), 86 HBV-infected hepatocellular carcinoma (HCC), and 107 HBV clearance group. Variations of CAII were genotyped using directly sequencing, Illumina’ sentrix array matrix chips, and high resolution melting (HRM). Biological significances by associated variations in CAII promoter was determined using luciferase reporter constructs.
We found that the novel insertion and seven variations, haplotype, and diplotype of CAII were significantly associated with increased susceptibility to only HCC patients (OR=0.457∼3.840 and P=0.049∼0.001). Functional analyses showed that common two haplotype (T-G-C-Ref and C-T-G-Ins) in promoter region has differential transcriptional activities.
Conclusions
Our findings suggest that altered expression by genetic variations of CAII may contribute the susceptibility of individuals to development and occurrence age of HCC.