HLA Alleles Cw12 and DQ4 in Kidney Transplant Recipients Are Independent Risk Factors for the Development of Posttransplantation Diabetes

Abstract

Background. The association between specific HLA alleles and risk for posttransplantation diabetes (PTDM) in a contemporary and multiethnic kidney transplant recipient cohort is not clear. Methods. In this single-center analysis, data were retrospectively analyzed for 1560 nondiabetic kidney transplant recipients at a single center between 2007 and 2018, with median follow-up of 33 mo (interquartile range 8-73). HLA typing methodology was by DNA analysis and reported at the resolution required for the national allocation scheme. Diagnosis of PTDM was aligned with International Consensus recommendations. Results. PTDM developed in 231 kidney transplant recipients. Exploring 99 HLA alleles, the presence of Cw12, B52, B38, B58, DQ4, A80, and DR13 and the absence of DQ3 and DR04 were associated with significant increases in PTDM risk. In a multivariable Cox regression model, adjusting for other clinical risk factors for PTDM, the presence of Cw12 (hazard ratio [HR], 1.57; 95% CI, 1.08-2.27; P = 0.017) and DQ4 (HR, 1.78; 95% CI, 1.07-2.96; P = 0.026) were found to be independent risk factors for PTDM. There was also evidence that the presence of B58 increases PTDM risk within the subgroup of recipients of White ethnicity (HR, 5.01; 95% CI,; P < 0.001). Conclusion. Our data suggest that specific HLA alleles can be associated with PTDM risk, which can be used pretransplantation for PTDM risk stratification. However, association is not causality, and this work requires replication and further investigation to understand underlying biological mechanisms.

An update review of post‐transplant diabetes mellitus: Concept, risk factors, clinical implications and management

“…38 The contribution of the human leukocyte antigen profile and immunologic mismatch to the development of PTDM is controversial, with some, but not all, studies revealing specific alleles, including Cw12, DQ-4 and B27, as independent risk factors for PTDM. 39,40 Moreover, graft rejection does not appear to be a risk factor for PTDM. 41 The potential associations between specific genes, human leukocyte antigen mismatch and graft rejection with the development of PTDM require further investigation.…”

“…Genes implicated in various processes critical to the pathogenesis of PTDM, such as pancreatic beta‐cell maturation, proliferation, apoptosis, insulin secretion, atherosclerosis of carotid arteries, obesity, mediators of inflammation, including interleukins, and other metabolic pathways, are shown to play a role in the development of PTDM 38 . The contribution of the human leukocyte antigen profile and immunologic mismatch to the development of PTDM is controversial, with some, but not all, studies revealing specific alleles, including Cw12, DQ‐4 and B27, as independent risk factors for PTDM 39,40 . Moreover, graft rejection does not appear to be a risk factor for PTDM 41 .…”