IL-6 Promoter Polymorphisms and Breast Cancer Susceptibility: A Meta-Analysis of 16,499 Cases and 21,186 Controls

Interleukin-6 (IL-6) plays a critical role in tumor microenvironment regulation and immune suppression, yet the association between IL-6 promoter polymorphisms and breast cancer risk remains inconsistent across populations. This meta-analysis comprehensively evaluates three major IL-6 promoter variants (rs1800795, rs1800796, and rs1800797) in relation to breast cancer susceptibility while addressing multifactorial genetic and environmental contributions. A systematic search of 18 international and regional databases was performed through July 2025 to identify case-control studies assessing IL-6 promoter polymorphisms and breast cancer risk. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under five genetic models. Subgroup analyses were performed by ethnicity and study design. Thirty case-control studies from 17 publications involving 33,350 participants (14,488 cases; 18,862 controls) from 13 countries were included. The rs1800796 polymorphism showed significant overall association with increased breast cancer risk in the allelic (OR = 1.193, 95% CI: 1.003-1.431, p = 0.046) and codominant models (OR = 1.339, 95% CI: 1.009-1.779, p = 0.043), with stronger effects in hospital-based cohorts. The rs1800795 variant demonstrated no overall association but exhibited significant Asian-specific effects under the recessive model (OR = 2.111, 95% CI: 1.361-3.274, p = 0.001). The rs1800797 polymorphism showed no association in any genetic model (allelic OR = 1.077, 95% CI: 0.855-1.356, p = 0.531) with negligible heterogeneity (I² = 0%). Substantial heterogeneity was observed for rs1800795 and rs1800796, reflecting differences in ethnicity, genotyping methods, and control recruitment strategies. The rs1800796 polymorphism represents a candidate genetic risk factor for breast cancer, particularly in Asian populations and hospital-based settings. These findings emphasize the necessity of population-stratified analyses, gene-environment interaction studies, and genotype-informed clinical trials before translating genetic associations into personalized therapeutic strategies.