Complex Linkage Disequilibrium Effects in HLA-DPB1 Expression and Molecular Mismatch Analyses of Transplantation Outcomes

Abstract

Background. HLA molecular mismatch (MM) is a risk factor for de novo donor-specific antibody (dnDSA) development in solid organ transplantation. HLA expression differences have also been associated with adverse outcomes in hematopoietic cell transplantation. We sought to study both MM and expression in assessing dnDSA risk. Methods. One hundred three HLA-DP-mismatched solid organ transplantation pairs were retrospectively analyzed. MM was computed using amino acids (aa), eplets, and, supplementarily, Grantham/Epstein scores. DPB1 alleles were classified as rs9277534-A (low-expression) or rs9277534-G (high-expression) linked. To determine the associations between risk factors and dnDSA, logistic regression, linkage disequilibrium (LD), and population-based analyses were performed. Results. A high-risk AA:GX (recipient:donor) expression combination (X = A or G) demonstrated strong association with HLA-DP dnDSA (P = 0.001). MM was also associated with HLA-DP dnDSA when evaluated by itself (eplet P = 0.007, aa P = 0.003, Grantham P = 0.005, Epstein P = 0.004). When attempting to determine the relative individual effects of the risk factors in multivariable analysis, only AA:GX expression status retained a strong association (relative risk = 18.6, P = 0.007 with eplet; relative risk = 15.8, P = 0.02 with aa), while MM was no longer significant (eplet P = 0.56, aa P = 0.51). Importantly, these risk factors are correlated, due to LD between the expression-tagging single-nucleotide polymorphism and polymorphisms along HLA-DPB1. Conclusions. The MM and expression risk factors each appear to be strong predictors of HLA-DP dnDSA and to possess clinical utility; however, these two risk factors are closely correlated. These metrics may represent distinct ways of characterizing a common overlapping dnDSA risk profile, but they are not independent. Further, we demonstrate the importance and detailed implications of LD effects in dnDSA risk assessment and possibly transplantation overall.

Improved detection of evolutionary selection highlights potential bias from different sequencing strategies in complex genomic-regions

“…Receptor genes, cell surface, signaling, and immune genes—especially HLA genes— are all categories of genes expected to be likely candidates for balancing or positive selection because their functionality is directly tied to environmental interactions, such as response to pathogens and sense of smell or taste, and hence they are subject to evolutionary pressures. The HLA genes are known to be difficult to properly sequence because they are highly polymorphic and contain large LD blocks; however, they are of vital importance to the immune system and detailed typing of solely the HLAs is performed in settings like transplantation where matching between patient and donors is critical to avoid organ rejection (Wiebe et al 2018; Petersdorf et al 2014; Shieh et al 2020). Dramatic signatures of selection in chromosome 6, in and around the MHC which contains HLA genes, were observed, including several of the top ten LD-ABF selection peaks across all populations and around 40% of the GWAS significantly associated variants occurring in the MHC.…”

“…The HLA genes are known to be difficult to properly sequence because they are highly polymorphic and contain large LD blocks; however, they are of vital importance to the immune system and detailed typing of solely the HLAs is performed in settings like transplantation where matching between patient and donors is critical to avoid organ rejection (Wiebe et al 2018;Petersdorf et al 2014;Shieh et al 2020 Analysis was run on genes containing at least 100 haplotypes for a given population.…”

“…Despite these observations and its profound importance to the fields of immunology, immunogenetics, and evolutionary biology, detailed follow up and characterization of the MHC and its HLA genes has been limited. Fortunately, due to the vital importance of HLA matching for avoiding rejection and graft versus host disease in organ and stem cell transplants, detailed typing of selective HLA genes is routinely performed in the clinical setting [34][35][36] .Taking advantage of this, we utilized high-resolution HLA typing data from the IHIW to take a closer look at balancing selection across these genes. This dataset consists of over 3,500 samples, each providing 2 alleles per HLA gene typed at 4 field resolution and represents a diverse set of world populations (see Methods).…”

“…Petersdorf et al 2014;Shieh et al 2020). Dramatic signatures of selection in chromosome 6, in and around the MHC which contains HLA genes, were observed, including several of the top…”

Identification of the novel HLA‐DPB1*03:01:14 allele by next‐generation sequencing in a Chinese cord blood donor

“…It has been reported that mismatching between a high‐expression HLA‐DPB1 alleles in the recipient and a low‐expression HLA‐DPB1 allele in the donor is associated with a high risk of graft‐versus‐host disease in recipients of hematopoietic cell transplantation (HCT), 1 and as such, HLA‐DPB1 allele compatibility is gradually being introduced for donor selection in HCT in some countries 2 . Currently, more than 1909 HLA‐DPB1 alleles have been identified around the world according to the IPD‐IMGT/HLA database release 3.47 version 3 .…”