A functional SNP of the Interleukin-18 gene is associated with the presence of hepatocellular carcinoma in hepatitis B virus-infected patients.
OBJECTIVE
The natural course of hepatitis B virus (HBV) infection is likely related to host immune factors. Interleukin-18 (IL-18) plays a significant role in immune defense. This study was undertaken to determine the association between the presence of hepatocellular carcinoma (HCC) and single-nucleotide polymorphisms (SNPs) in the IL-18 gene in HBV-infected patients.


METHODS
Between March 2002 and December 2004, 730 Korean subjects were enrolled in two different groups: (1) chronic carrier without HCC (n=637) and (2) HCC (n=93). We analyzed SNPs at four polymorphic sites in the IL-18 gene at positions -667G>T, -148G>C, +8925C>G, and +13925A>C in the study subjects. To evaluate the functional significance of SNPs in the IL-18 gene promoter region, we performed a reporter gene assay in HepG2 and Hep3B cells transfected with different alleles.


RESULTS
The IL-18 -148C allele, +8925G allele, +13925C allele, and haplotype 3 (TCGC) were associated with the presence of HCC in codominant and dominant models. Furthermore, functional analyses using the reporter gene assay revealed that the -148C allele conferred significantly lower promoter activity.


CONCLUSIONS
This study indicates that the -148C, +8925G, and +13925C alleles of the IL-18 gene are associated with the presence of HCC and the 148G>C SNP is functionally important in determining disease outcome.
Kim
Yong Seok
YS
Department of Biochemistry and Molecular Biology, Hanyang University College of Medicine, Seoul, South Korea.
Cheong
Jae Youn
JY
Cho
Sung Won
SW
Lee
Kee Myung
KM
Hwang
Jae Chul
JC
Oh
Bermseok
B
Kimm
Kuchan
K
Lee
Jung A
JA
Park
Byung Lae
BL
Cheong
Hyun Sub
HS
Shin
Hyoung Doo
HD
Kim
Jin Hong
JH
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000276:immunology / Q000821:virology; D005260:Female; D005787:Gene Frequency; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D056945:Hep G2 Cells; D019694:Hepatitis B, Chronic / Q000235:genetics* / Q000276:immunology; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics* / Q000378:metabolism; D015810:Linkage Disequilibrium; D008103:Liver Cirrhosis / Q000235:genetics / Q000276:immunology / Q000821:virology; D008113:Liver Neoplasms / Q000235:genetics* / Q000276:immunology / Q000821:virology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D056910:Republic of Korea; D018570:Risk Assessment; D012307:Risk Factors; D014162:Transfection
D020382:Interleukin-18