High-Resolution NGS HLA Typing Identifies Specific Class II-Dominant Risk Haplotypes and HLA LD Structure in Acute...

Acute lymphoblastic leukaemia (ALL) results from the uncontrolled growth of lymphoid progenitors, yet the immunogenetic factors behind this remain poorly understood. A connection between specific HLA alleles, multi-locus haplotypes and ALL predisposition was suggested, with an ethnic component to this association. This retrospective case-control study analysed 137 ALL cases and 350 ethnically-matched controls using six-digit NGS typing of HLA-A, -B, -C, -DRB1, -DQA1, -DQB1 and -DPB1 loci. Allele and haplotype differences were tested by χ²/Fisher's exact methods with age- and sex-adjusted logistic regression and Bonferroni/BH-FDR correction. HLA haplotypes were generated using EM algorithms, and linkage disequilibrium (LD) was measured using ΔLD heatmaps. HLA Class I (C, B) and Class II (DRB1, DQA1, DQB1) alleles with strong, population-specific links to ALL were identified in ethnic Kazakhs. Notable variants, including C*03:02:02, C*04:01:01, C*02:02:02, C*12:02:02, B*40:01:02 and B*27:05:02, as well as DRB1*14:54:01, DRB1*14:24:01 and DQB1*02:02:01, were found exclusively in cases. ΔLD analysis revealed structured, locus-specific LD changes, with the most significant deviations involving DQA1/DQB1/DPB1 interactions. Class I haplotypes A*33:03:01~C*03:02:02~B*58:01:01 and A*33:03:01~C*03:02:01~B*58:01:01 showed positive and negative associations with ALL risk, respectively. Five Class II haplotypes, including DRB1*07:01:01~DQA1*01:02:01~DQB1*02:02:01~DPB1*04:01:01 and DRB1*15:01:01~ DQA1*05:05:01~DQB1*06:02:01~DPB1*04:02:01, were also strongly linked to a high ALL risk. In conclusion, NGS-based high-resolution typing identified novel, population-specific HLA associations with ALL in ethnic Kazakhs, with Class II effects predominating and additional Class I signals at HLA-B and HLA-C. This provides the first detailed immunogenetic framework for ALL in Central Asia, highlighting the significance of population-tailored HLA analyses for refining ALL risk assessment.