HLA-B leader genotypes in a clinical population.

Area of Science:

• Immunogenetics
• Transplantation immunology
• Molecular biology

Background:

• The -21 dimorphism in HLA-B exon 1 leader sequences is linked to graft-versus-host disease (GVHD), relapse, and survival after hematopoietic cell transplantation (HCT).
• Prospective donor selection for HCT could be improved by considering this leader dimorphism, but requires knowledge of its frequencies in patients and donors.

Purpose of the Study:

• To determine the frequencies of the HLA-B leader dimorphism (rs1050458) and its association with HLA-B Bw4/Bw6 and C1/C2 KIR epitopes.
• To analyze the dimorphism's prevalence in a large cohort of patients and transplant donors.

Main Methods:

• High-resolution HLA typing of over 5500 subjects (11,126 haplotypes) using TruSight/AlloSeq NGS.
• Analysis of rs1050458 variants in HLA-B exon 1 to define T-leader and M-leader sequences.
• Definition of HLA-B Bw4/Bw6 and C1/C2 KIR epitopes based on established nomenclature.

Main Results:

• The HLA-B leader dimorphism was confirmed, with 70% of haplotypes encoding T-leader and 30% encoding M-leader sequences.
• Genotype frequencies (TT, MT, MM) were consistent across patient, related, and unrelated donor groups.
• Associations between M/T leader, Bw4/Bw6, and C1/C2 KIR epitopes were identified, enhancing understanding of Class I innate immune response features.

Conclusions:

• The rs1050458 leader dimorphism is prevalent in patients and transplant donors.
• This dimorphism is associated with specific HLA-B Bw4/Bw6 and C1/C2 KIR features, providing insights into innate immunity in transplantation.
• Understanding these frequencies and associations may inform donor selection strategies to mitigate HCT risks.