An In‐Depth Review of the Genetics of the Non‐Classical HLA Class I Gene HLA‐E and Its Effects on Haematopoietic Cell Transplant Outcomes

HLA‐E is a non‐classical HLA class I gene with limited reported genetic variability and few published studies into full‐gene sequencing or population allele frequencies. Two protein variants, HLA‐E*01:01 and HLA‐E*01:03 , are very common, accounting for 94%–100% of observed alleles in most studies performed to date. Frequently utilised exon‐based sequencing strategies have led to the assumption of HLA‐E being a near bi‐allelic gene; however, recent full‐gene sequencing studies have shown a greater degree of genetic variability than initially imagined. We carried out a literature review of HLA‐E genotype and ethnicity data, which suggested HLA‐E*01:03 is more common in Asian and, in particular, East Asian populations. Furthermore, HLA‐E*01:03:02 is more frequently observed than HLA‐E*01:03:01 in European and American populations, whereas HLA‐E*01:03:01 is found at higher frequencies in Asian populations. It has been proposed that HLA‐E may have a role in Haematopoietic Cell Transplantation (HCT) due to its interaction with NK and CD8 + T cells and its non‐canonical peptide binding repertoire. Here we also review published literature into the effects of HLA‐E genetics on HCT outcomes. Heterogeneity between cohorts muddies the waters; hence, studies report confounding effects of HLA‐E genotype and matching on HCT outcomes. The need for further HLA‐E sequencing of larger cohorts is evident to gain useful insight into the true genetic variability of HLA‐E and its impact on HCT.