Quality-Controlled Analysis of KLRK1/NKG2D Polymorphisms and Haplotypes in Bulgarian Patients with Oral Squamous Cell Carcinoma

Background/Objectives: Natural killer group 2D (NKG2D), encoded by KLRK1, contributes to the immune recognition of stressed and transformed epithelial cells through interactions with MICA and MICB ligands. Previous work from our group implicated MICA/MICB variation in Bulgarian patients with oral squamous cell carcinoma (OSCC), but the receptor-side contribution of KLRK1 has not been examined in the same disease context. Methods: Five candidate KLRK1 single-nucleotide polymorphisms were initially evaluated in 69 OSCC patients and 105 Bulgarian controls. After anatomical review, one maxillary sinus and one soft palate case were excluded from the primary strict OSCC cohort. Hardy–Weinberg equilibrium, genotype call rates, differential missingness, genotype and allele counts, additive logistic regression, MICA-129-adjusted models, age-overlap sensitivity analyses, and four-marker haplotypes were assessed. Results: The final primary cohort included 67 strict OSCC cases and 105 controls. rs2255336 deviated significantly from Hardy–Weinberg equilibrium in controls and was excluded from primary inference. Among the four retained variants (rs2617170, rs2246809, rs2617160, and rs1049174), no statistically detectable association with OSCC was observed after adjustment for age and sex or after additional adjustment for MICA-129 genotype. The four-marker haplotype analysis was also non-significant. Conclusions: In this QC-aware exploratory analysis, the KLRK1 variants retained after Hardy–Weinberg filtering were not detectably associated with OSCC. These negative findings should be interpreted cautiously because of the limited power, differential genotype missingness, age and sex imbalance, absence of ancestry principal components, and lack of tobacco, alcohol, and HPV data.