Host immunogenetics and EBV detection in cancer: the CTLA-4 rs231775 signal in a multi-cancer case–control cohort

Persistent oncogenic viruses are common in cancer and may be modulated by host immunogenetics. We evaluated whether CTLA-4 and IL-4 variants are associated with qualitative viral DNA detection, focusing on EBV, in a multi-cancer case–control cohort. 90 cancer patients and 90 age-/sex-matched controls were enrolled from Southern Iraq. Peripheral blood (and tumor DNA when available) was assayed by qualitative EBNA-1 PCR for EBV, and by PCR for HPV and HBV. CTLA-4 (rs231775, rs5742909) and IL-4 (rs2243250) were genotyped. The associations were tested by χ² and multivariable logistic regression, including adjustment for cancer type, and discrimination was assessed by ROC AUC. Among 180 participants, viral DNA was detected in 59 of 90 cancer patients (65.6%) and in none of the 90 controls (χ²[1, n = 180] = 84.82; p < 0.001). Among cases, positivity rates were 26.8% for HBV, 21.4% for EBV, and 17.9% for HPV. Genotype–phenotype analyses showed enrichment of the CTLA-4 rs231775 GA genotype among EBV-positive cases (χ² p = 0.0105). In multivariable models adjusted for age, sex, cancer type, and routine hematology, rs231775-GA remained independently associated with EBV positivity (p = 0.030), and the model yielded an AUC of 0.75. No EBV associations were observed for rs5742909 or IL-4 rs2243250. Hematological indices were within reference ranges and did not differ by EBV status, and the rs231775 finding was independent of these measures. Because EBV DNA was undetectable in all controls, the association reflects within-case differences (EBV+ vs. EBV–), and results should be interpreted as hypothesis-generating. In this multi-cancer cohort, CTLA-4 rs231775 (GA) is associated with detectable EBV DNA by qualitative PCR, independent of age, sex, cancer type, and routine hematology, highlighting an immune-checkpoint genetic pathway that may facilitate EBV persistence. Findings for rs5742909 and IL-4 rs2243250 were null for EBV. These data support exploratory, targeted studies to validate CTLA-4–mediated susceptibility to EBV in cancer using quantitative assays and larger, multi-center designs.