HLA homozygosity is associated with Non-Hodgkin lymphoma.

The "heterozygote advantage" hypothesis has been postulated regarding the role of human leukocyte antigen (HLA) in non-Hodgkin lymphoma (NHL), where homozygous loci are associated with an increased risk of disease. In this retrospective study, we analyzed the HLA homozygosity of 3789 patients with aplastic anemia (AA), acute lymphocytic leukemia (ALL), acute myeloblastic leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL) at HLA-A, B, C, DRB1 and DQB1 loci compared to 169,964 normal controls. HLA homozygosity at one or more loci was only associated with an increased risk in NHL patients (OR = 1.28, 95% CI [1.09, 1.50], p = 0.002). This association was not seen in any of the other hematologic diseases. Homozygosity at HLA-A alone, HLA-B + C only, and HLA-DRB1 + DQB1 only was also significantly associated with NHL. Finally, we observed a 17% increased risk of NHL with each additional homozygous locus (OR per locus = 1.17, 95% CI [1.08, 1.25], p trend = 2.4 × 10-5). These results suggest that reduction of HLA diversity could predispose individuals to an increased risk of developing NHL.

Adequate tacrolimus exposure modulates the impact of HLA class II molecular mismatch: a validation study in an American cohort.

Clinicians have few tools to predict the risk of alloimmune injury that would guide immunosuppression management in renal transplant patients. We evaluated human leukocyte antigen (HLA)-DR/DQ molecular mismatch to predict de novo donor-specific antibodies (DSAs) during the first year of transplant and explored how differences in tacrolimus exposure may modulate this risk. HLA-DR and -DQ eplet mismatches were determined between 444 donor-recipient pairs in Denver, Colorado between 2007 and 2013. Previously defined mismatch thresholds stratified recipients into low- (N = 119), intermediate- (N = 153), and high- (N = 172) risk categories. The area under the curve for DSA at 1 year was 0.84 and 0.82 for HLA-DR and HLA-DQ eplet mismatches, respectively. Compared to low-risk patients, there was a graded increase in risk of DR/DQ DSA in intermediate (HR 15.39, 95% CI 2.01-118.09, p = .009) and high-risk (HR 23.81, 95% CI 3.17-178.66, p = 0.002) categories. Intermediate- and high-risk patients with a mean tacrolimus <6 ng/ml versus >8 ng/ml had increased risk of DR/DQ DSA at 1 year (HR 2.34, 95% CI 1.05-5.22, p = .04). HLA molecular mismatch represents a reproducible, objective, and clinically relevant tool to stratify patients by alloimmune risk and may help guide personalized immunosuppression management.