Genetics of New-Onset Diabetes after Transplantation

Abstract

New-onset diabetes after transplantation is a common complication that reduces recipient survival. Research in renal transplant recipients has suggested that pancreatic b-cell dysfunction, as opposed to insulin resistance, may be the key pathologic process. In this study, clinical and genetic factors associated with new-onset diabetes after transplantation were identified in a white population. A joint analysis approach, with an initial genome-wide association study in a subset of cases followed by de novo genotyping in the complete case cohort, was implemented to identify single-nucleotide polymorphisms (SNPs) associated with the development of new-onset diabetes after transplantation. Clinical variables associated with the development of diabetes after renal transplantation included older recipient age, female sex, and percentage weight gain within 12 months of transplantation. The genome-wide association study identified 26 SNPs associated with new-onset diabetes after transplantation; this association was validated for eight SNPs (rs10484821, rs7533125, rs2861484, rs11580170, rs2020902, rs1836882, rs198372, and rs4394754) by de novo genotyping. These associations remained significant after multivariate adjustment for clinical variables. Seven of these SNPs are associated with genes implicated in b-cell apoptosis. These results corroborate recent clinical evidence implicating b-cell dysfunction in the pathophysiology of newonset diabetes after transplantation and support the pursuit of therapeutic strategies to protect b cells in the post-transplant period. One-year graft survival after renal transplantation is now excellent, exceeding 93% for organs donated after brain death and 96% for those from living donors. 1-3 Technical advancements in surgery, improved understanding of immunology, and innovative developments in pharmacology have altered the landscape of renal transplantation. The goal of preventing early graft loss has largely been achieved and arguably the greatest challenge now is the avoidance of late graft failure. Although there has been a considerable improvement in 1-year renal transplant survival, the rate of graft attrition after the first year remains frustratingly constant. 2,4 New-onset diabetes after transplantation (NODAT) is a common and serious disorder that curtails recipient survival. [5][6][7] NODAT is associated with cardiovascular complications [8][9][10][11] and develops in 2%-50% 12 of renal transplant recipients. Approximately 50% of recipients with NODAT require insulin therapy. [6][7][8][13][14][15] A number of clinical variables have been associated with NODAT, including black ethnicity, older recipient age, female sex, obesity, immunosuppression, and viral infections. 5,6,8,13,16,17 Until recently, the pathophysiology of NODAT was considered to be analogous to type 2 diabetes mellitus. Renal transplant recipients have increased insulin resistance compared with transplant-naïve persons with normal renal function. 18 In a nondiabetic renal transplant population, the m...

Dynamics of Glucose Metabolism After Kidney Transplantation

“…PTDM differs from type 2 diabetes in the general population as far as the relative contribution of insulin secretion and -sensitivity is concerned [5]. Genetics, as an inherent predisposition, has been shown to play a role in PTDM [9]. Our finding of substantial patient fluxes, however, may point towards a contribution of external, fluctuating factors in a post-transplant setting.…”

“…As in type 2 diabetes, reduced ß-cell function will eventually result in overt PTDM [5]. This is underlined by the fact that PTDM and type 2 diabetes share several risk genes, most of which affect ß-cell function [9, 10]. In addition to the classic risk factors, other transplant-specific factors such as immunosuppression contribute to the overall risk of developing PTDM [11, 12].…”

Association of leptin receptor gene polymorphisms with post-transplant diabetes mellitus: Short report and literature review

“…To overcome these limitations, alternative approaches such as genome-wide association studies (GWAS) and meta-analyses are performed. McCaughan et al [2] performed GWAS with secondary validation. They reported 26 SNPs that were associated with PTDM, and the association was validated for 8 SNPs.…”

“…It affects 2-50% of renal transplant recipients and is associated with graft failure, cardiovascular complications, infection, and mortality [2,3]. As in type 2 diabetes mellitus (T2DM), decreased insulin secretion, increased insulin resistance, or a combination of both are believed to be involved in PTDM [3,4].…”

Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study

“…Genome‐wide association studies (GWAS) have contributed greatly to an increased understanding of complex common conditions such as inflammatory bowel disease, hypertension, type 2 diabetes, and schizophrenia 21. A small number of GWAS have been reported in the field of renal transplantation, describing SNPs associated with cardiovascular adverse events in recipients taking calcineurin inhibitor immunosuppression,22 2 SNPs associated with serum creatinine levels at 5 years posttransplant,23 and a number of SNPs associated with the development of new‐onset diabetes after transplantation 24. Recently, a GWAS using pooled DNA of recipient‐only origin found variation in 2 new loci associated with acute rejection in both univariate and multivariate analysis 25.…”