Genetic polymorphisms in the cytokine genes and the risk of hepatocellular carcinoma.

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Hepatocellular carcinoma (HCC) is the fifth most common cancer in men worldwide (Parkin et al., 2002). Although this is a rare malignancy among non-Asians in the US, the incidence of HCC has doubled over the past two decades (El-Serag et al., 1999). Chronic hepatitis B and C are established etiological factors for HCC. Recent results suggested that genetic variations in cytokine genes responsible for inflammatory and immune responses are associated with risk of HCC among a Chinese population (Nieters et al., 2005). The objective of the present study was to assess the association between the genetic polymorphisms in the cytokine genes and risk of HCC in non-Asian Americans.
 The study consists of 120 black and white HCC cases confirmed by histopathology, and 230 controls matched by age, sex and race in Los Angeles County, California. The information on the demographics, lifestyle, and medical history was acquired through questionnaires. Genetic variants in the interferon γ (IFNγ), tumor necrosis factor α (TNFα), interleukin-2 (IL-2), IL-4, IL-6, IL-10, IL-12 and IL-18 genes were determined by Taqman assays. Hepatitis B surface antigen (HBsAg), antibodies to hepatitis B core antigen (anti-HBc) and antibodies to hepatitis C (anti-HCV) in serum were measured by ELISA. The logistic regression method was used to analyze the data. The strength of the associations between individual and combined genotypes and HCC risk was assessed by odds ratios (ORs) and their 95% confidence intervals. The logistic models included age, sex, race, number of alcoholic drinks per day, and the hepatitis B/C.
 Relative to the putative high-activity genotypes, each individual low activity genotype of Th1 genes IFNγ, TNFα, IL-6, IL-12 and IL-18 was associated with statistically nonsignificant increase in HCC risk (e.g., OR=1.47, 95% CI=0.85-2.57 for the GG versus GCC/GC genotypes of the IL-6). The risk increased with increasing number of low-activity genotypes of T-helper (Th) 1 cytokine genes; the OR was 4.10 (CI=0.95-17.78) for 5 versus zero or one low activity genotypes. For Th2 cytokines (IL-4 and IL-10), low activity genotypes were associated with statistically nonsignificant decrease in HCC risk. The risk decreased with increasing number of low activity Th2 genotypes; the OR was 0.64 (CI=0.27-1.55) for two versus zero low activity genotypes. When the Th1 and Th2 genotypes were combined together, the inverse association between the number of low-activity Th2 genotypes and HCC risk was more apparent among individuals possessing 4 or more low-activity Th1 genotypes (OR =0.04, 95% CI = 0.004-0.52) for two versus zero low-activity Th2 genotypes. In conclusion, low activity Th1 cytokine genotype examined was associated with nonsignificant increase in HCC risk. Conversely, low activity Th2 cytokine genotype was associated with decreased risk of HCC in US non-Asians.