Independent and Additive Interactive Effects Among Tumor Necrosis Factor-α Polymorphisms, Substance Use Habits, and Chronic Hepatitis B and Hepatitis C Virus Infection on Risk for Hepatocellular Carcinoma

We conducted a case-control study to assess the roles of tumor necrosis factor (TNF)-α polymorphisms, substance use habits, and chronic hepatitis B virus (HBV)/hepatitis C virus (HCV) infection on the risk for hepatocellular carcinoma (HCC). We enrolled 200 pairs of sex- and age-matched patients with HCC and unrelated healthy controls. TNF-α polymorphisms were detected with polymerase chain reaction and direct sequencing. Serum hepatitis B surface antigen (HBsAg) and antibodies to HCV (anti-HCV) were detected. We used a structured questionnaire to obtain information about substance use habits. Multivariate analysis indicated that TNF308.2 allele (odds ratio [OR], 3.23; p = 0.011), habitual betel quid chewing (OR, 3.70; p = 0.011), HBsAg (OR, 23.62; p = 0.0001), and anti-HCV (OR, 38.73; p = 0.0001) were independent risk factors for HCC. Having at least 2 substance use habits was associated with risk for HCC. The more substance use habits, the higher the OR for HCC (pfor trend = 0.0001). There were additive interactions among TNF308.2 allele, substance use habits, and chronic HBV/HCV infection. Multivariate analysis indicated that TNF308.2 allele (p = 0.001), cigarette smoking (p = 0.0001), and alcohol drinking (p = 0.0001) were independent risk factors for habitual betel quid chewing. Moreover, patients harboring the TNF308.2 allele and/or those with habits of substance use had low serum albumin concentration and platelet count (each p = 0.0001). In conclusion, there are independent and additive interactive effects among the TNF308.2 allele, substance use habits, and chronic HBV/HCV infection on the risk for HCC. Substance use habits or carrying the TNF308.2 allele correlates with disease severity and hepatic fibrosis, which may contribute to higher risks for HCC. Abbreviations: ALT = alanine aminotransferase, anti-HCV = antibodies to hepatitis C virus, CI = confidence interval, EIA = enzyme immunoassay, HBsAg = hepatitis B surface antigen, HBV = hepatitis B virus, HCC = hepatocellular carcinoma, HCV = hepatitis C virus, NF-κB = nuclear factor-κB, OR = odds ratio, PCR = polymerase chain reaction, SNP = single nucleotide polymorphism, TNF = tumor necrosis factor.