NKG2D genetic variants and cancer susceptibility: Integrating case-control evidence with meta-analysis

Lymphomas are biologically heterogeneous malignancies with multifactorial etiologies involving genetic, environmental, and immune dysregulation. The functional variant rs1049174 SNP in the KLRK1 gene (encoding NKG2D) regulates NKG2D expression and modulates NK cells immune surveillance pathways, which may influence lymphoma susceptibility. We investigated this association through a two-stage case-control study and meta-analysis. First, we analyzed 246 diffuse large B-cell lymphoma (DLBCL) patients and 599 healthy controls (exploratory cohort), followed by a confirmatory cohort of 234 non-Hodgkin lymphoma (NHL)/Hodgkin lymphoma (HL) patients. Genotype frequencies were assessed via chi-square tests, with odds ratios (ORs) calculated for risk associations. A systematic review and meta-analysis of 10 studies, including our cohorts (3,785 cases and 4,129 controls), testing rs1049174 and cancer risk was also conducted. In the exploratory cohort, the GG genotype showed no significant association with overall lymphoma risk (OR = 0.83; 95% CI: 0.61-1.13; *p* = 0.25). However, in NHL, the GG genotype was underrepresented (OR = 0.75; 95% CI: 0.57-0.99; *p* = 0.02). Pooled lymphoma analysis revealed a protective effect (OR = 0.78; 95% CI: 0.62-0.99; *p* = 0.03). Meta-analysis confirmed a significant protective role of the GG genotype against cancer (OR = 0.71; 95% CI: 0.63-0.79), despite heterogeneity and potential publication bias. Our findings suggest that the rs1049174 GG genotype is associated with reduced lymphoma susceptibility, particularly in NHL, underscoring the importance of immunogenetic variants in lymphomagenesis. Further functional and clinical studies are needed to elucidate the mechanistic basis of this association.