Polymorphisms of the IL-1 gene complex are associated with alcohol dependence in Spanish caucasians: Data from an association study

Background: There is growing evidence for involvement of pro-inflammatory cytokines in alcohol dependence. The aim of this study was to investigate whether 4 functionally relevant polymorphisms of the interleukin-1 (IL-1) and tumor necrosis factor-alpha genes were associated with alcohol dependence and with measures of clinical severity and treatment outcome. Methods: Two hundred alcohol-dependent (AD) patients and 420 healthy controls from the same Spanish Caucasian population were genotyped using standard methods. Baseline and 6-month assessments included alcohol intake, addiction severity, and biomarkers of alcohol intake. Results: Alcohol-dependent patients showed an excess of IL-1α-889 C/T [50.8% vs. 39.3%, χ² (df) = 7.30 (2), uncorrected p = 0.026, corrected p = 0.104] and IL-1RA (86 bp)_n A1/A1 genotypes [64.8% vs. 50.8%, χ² (df) = 12.65 (3), corrected p = 0.020]. The A1/A1 excess was associated with alcohol dependence only in men [69.9% vs. 49.5%, χ² (df) = 15.72 (2), corrected p < 0.001]. Six-month clinical and hematological outcome measures did not vary by genotype of the 4 polymorphisms. Haplotype analysis revealed an excess of the IL-1α-889 C/IL-1β +3953 C/IL-1RA A2 haplotype in the control group compared with AD patients [20.0% vs. 14.1%, χ² (df) = 7.25 (1), p = 0.007; odds ratio (OR) = 0.64, 95% confidence interval (CI) = 0.46-0.89] and in the abstainers after 6 months of treatment compared with nonabstinent patients [14.7% vs. 6.2%, χ² (df) = 5.65 (1), p = 0.017; OR = 2.56, 95% CI = 1.15-5.62]. Conclusions: Our findings provide further tentative evidence of the role of IL-1 in alcohol dependence as well as evidence that the nature of the associations may be direct, gender-specific, or involve haplotype effects. However, findings from single association studies constitute tentative knowledge and must be interpreted carefully and precise replication is required.