High‐Resolution NGS HLA Typing Identifies Specific Class II –Dominant Risk Haplotypes and HLA LD Structure in Acute Lymphoblastic Leukaemia Among Ethnic Kazakhs

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 χ 2 /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.