Establishment of NGS-based HLA 9-locus haplotypes in the Eastern Han Chinese population highlights the role of HLA-DP in donor selection for transplantation

We collected HLA typing data from 653 families in the Eastern Han Chinese population. HLA-A, B, C, DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, DPA1, and DPB1 (HLA-11 loci) typing of 1781 subjects was performed using a commercial next-generation sequencing (NGS) method in our laboratory. The phasing of haplotypes in each family was determined by Mendelian segregation. Haplotype analysis revealed 1634 different haplotypes among a total of 2230 haplotypes. The predominant haplotype was A*30:01-C*06:02-B*13:02-DRB1*07:01-DRB4*01:03-DQA1*02:01-DQB1*02:02-DPA1*02:01-DPB1*17:01 (HF = 4.04%), followed by A*02:07-C*01:02-B*46:01-DRB1*09:01-DRB4*01:03-DQA1*03:02-DQB1*03:03-DPA1*02:02-DPB1*05:01 (HF = 1.84%) and A*33:03-C*03:02-B*58:01-DRB1*03:01-DRB3*02:02-DQA1*05:01-DQB1*02:01-DPA1*01:03-DPB1*04:01 (HF = 1.48%), accounting for 7.35% of the total. Meanwhile 76.41% of all haplotypes were observed only once or twice (HF < 0.1%). Different from HLA-DRB3/4/5 and DQA1 loci, DP linkage markedly increased haplotype variation by 34.82% based on the 5-locus haplotype. The much weaker linkage disequilibrium (LD) of DQB1-DPB1 indicated the reason. We observed 10 analyzable recombination events, most of which occurred at DP loci. Even with the same common 5-locus haplotype, HLA-DP linkage alters the haplotype diversity and frequency. Analysis of related haplotype assignment and unrelated recipient-donor pairs matching at the 9-locus haplotype revealed that HLA-DP affects the donor selection strategy. Haplotype study of a large sample size using NGS identified linkage haplotypes beyond the 5 loci. LD, recombination events, and haplotype variation caused by DP loci emphasized that HLA 9-locus haplotype matching should be considered in donor selection, particularly the effect of DP loci. The finding lays the foundation for further studies on the effect of HLA-DP mismatch on transplantation.

Automated summary

In this study, HLA typing data from 653 families in the Eastern Han Chinese population were collected. HLA-A, B, C, DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, DPA1, and DPB1 (HLA-11 loci) typing was performed using a commercial next-generation sequencing (NGS) method. Haplotype analysis revealed different haplotypes, with the predominant haplotype being A*30:01-C*06:02-B*13:02-DRB1*07:01-DRB4*01:03-DQA1*02:01-DQB1*02:02-DPA1*02:01-DPB1*17:01. The study also found that HLA-DP affects the donor selection strategy and emphasized the importance of considering 9-locus HLA haplotype matching, particularly the effect of DP loci.