ABSTRACT
The National Marrow Donor Program maintains a registry of volunteer donors for patients in need of a hematopoietic stem cell transplantation. Strategies for selecting a partially HLA-mismatched donor vary when a full match cannot be identified. Some transplantation centers limit the selection of mismatched donors to those sharing mismatched antigens within HLA-A and HLA-B cross-reactive groups (CREGs). To assess whether an HLA mismatch within a CREG group ("minor") may result in better outcome than a mismatch outside CREG groups ("major"), we analyzed validated outcomes data from 2709 bone marrow and peripheral blood stem cell transplantations. Three-hundred and ninety-six pairs (15%) were HLA-DRB1 allele matched but had an antigen-level mismatch at HLA-A or HLA-B. Univariate and multivariate analyses of engraftment, graft-versus-host disease, and survival showed that outcome is not significantly different between minor and major mismatches (P = .47, from the log-rank test for Kaplan-Meier survival). However, HLA-A, HLA-B, and HLA-DRB1 allele-matched cases had significantly better outcome than mismatched cases (P < .001). For patients without an HLA match, the selection of a CREG-compatible donor as tested does not improve outcome.
Subject(s)
Hematologic Neoplasms/mortality , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Histocompatibility Testing , Living Donors , Peripheral Blood Stem Cell Transplantation , Alleles , Cross-Sectional Studies , Disease-Free Survival , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , HLA-A Antigens , HLA-B Antigens , HLA-DR Antigens , HLA-DRB1 Chains , Hematologic Neoplasms/complications , Humans , Male , Registries , Retrospective Studies , Survival RateABSTRACT
The aim of this study was to identify major histocompatibility complex alleles associated with the development and clinical features of inflammatory bowel disease (IBD). Genotyping at the human leukocyte antigen (HLA) DRB1 and DQB1 loci was performed on individuals from 118 Caucasian IBD sibling pair families and on 216 healthy controls. Both population- and family-based association tests were used to analyze data obtained on the entire study population and on clinical subgroups stratified by diagnosis, ethnicity, and disease distribution. HLA DRB1*0103 was significantly associated with IBD (OR = 6.0, p = 0.0001) in a case-control analysis of non-Jewish IBD-affected individuals. This association was apparent among both Crohn's disease (OR = 5.23, p = 0.0007) and ulcerative colitis (OR = 7.9, p = 0.0001) patients and was confirmed in the non-Jewish IBD population by results of family-based association analysis using the transmission disequilibrium test. HLA DQB1*0501 was also associated with IBD (OR = 1.64, p = 0.02) in the non-Jewish population. but statistically significant association of this allele with disease was not detected for Crohn's disease and ulcerative colitis separately. No significant associations were identified among the Jewish patients. In the non-Jewish IBD families, IBD was as strongly associated with the DRB1*0103 DQB1*0501 haplotype as with the DRB1*0103 allele alone. The carrier frequency of the DRB1*0103 allele was found to be 10-fold higher in Crohn's disease patients with pure colonic involvement than in healthy controls (38.5% vs. 3.2%; p = 0.0002). These data demonstrate the association of the HLA DRB1*0103 allele with both Crohn's disease and ulcerative colitis and with large intestine-restricted disease in non-Jewish IBD patients and therefore identify HLA DRB1*0103 as a potentially important contributor to disease susceptibility and to expression of colonic involvement in IBD.
