Clinical Immunogenetics Laboratory, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington, USA.
HLA. 2023 Jul;102(1):44-51. doi: 10.1111/tan.15022. Epub 2023 Mar 16.
The -21 dimorphism in the leader sequences of HLA-B exon 1 is associated with risk of graft-versus-host disease (GVHD), relapse and overall survival after unrelated donor hematopoietic cell transplantation (HCT), haploidentical HCT and cord blood transplantation. Consideration of the leader dimorphism in the prospective selection of allogeneic donors for HCT may help to lower risks for patients, but requires understanding of the frequencies of the leader in patients and candidate transplant donors. We defined the frequencies of the HLA-B leader, and its association to HLA-B Bw4/Bw6 and C1/C2 KIR epitopes. Sequence variants of rs1050458 of exon 1 position -21 for 11,126 haplotypes were analyzed from high resolution HLA typing of over 5500 study subjects. HLA typing was performed by TruSight/AlloSeq NGS and analyzed using TruSight/AlloSeq Assign software. HLA-B Bw4/Bw6 and C1/C2 KIR epitopes were defined based on established sequence alignments and nomenclature. Alleles at rs1050458 of HLA-B exon 1 were validated as dimorphic: rs1050458-C or -T variants encoding threonine (T) or methionine (M) at anchor position 2 (P2) of nonameric HLA-B leader peptides, respectfully. No additional variants were observed. Among study subjects, 70% of HLA-B haplotypes encoded T-leader and 30% encoded M-leader sequences. The genotype frequencies of TT, MT, and MM were consistent among patient, related, and unrelated donor groups. The associations of M/T leader, Bw4/Bw6, and C1/C2 enhanced understanding of the Class I features involved in the innate immune response. A population of patients and transplant donors confirms the rs1050458 leader dimorphism and its association with HLA-B Bw4/Bw6 and C1/C2 KIR features.
HLA-B 外显子 1 前导序列的-21 二态性与无关供者造血细胞移植（HCT）、半相合 HCT 和脐血移植后移植物抗宿主病（GVHD）、复发和总生存风险相关。在 HCT 中对同种异体供者进行前瞻性选择时考虑前导二态性可能有助于降低患者风险，但需要了解患者和候选移植供者前导的频率。我们定义了 HLA-B 前导的频率及其与 HLA-B Bw4/Bw6 和 C1/C2 KIR 表位的关联。从超过 5500 名研究对象的高分辨率 HLA 分型中分析了 11126 个单倍型外显子 1 位置-21 的 rs1050458 序列变异。HLA 分型通过 TruSight/AlloSeq NGS 进行，并使用 TruSight/AlloSeq Assign 软件进行分析。根据已建立的序列比对和命名法定义了 HLA-B Bw4/Bw6 和 C1/C2 KIR 表位。HLA-B 外显子 1 上 rs1050458 的等位基因被证实为二态性：rs1050458-C 或-T 变异分别编码非九聚体 HLA-B 前导肽 P2 处的苏氨酸（T）或蛋氨酸（M）。未观察到其他变体。在研究对象中，70%的 HLA-B 单倍型编码 T-前导序列，30%编码 M-前导序列。TT、MT 和 MM 的基因型频率在患者、相关和无关供者群体中一致。M/T 前导、Bw4/Bw6 和 C1/C2 的关联增强了对先天免疫反应中涉及的 I 类特征的理解。患者和移植供者群体证实了 rs1050458 前导二态性及其与 HLA-B Bw4/Bw6 和 C1/C2 KIR 特征的关联。
