Abstract
New Onset Diabetes After Transplantation (NODAT) is a serious metabolic complication. While β-cell dysfunction is considered the main contributing factor in the development of NODAT, the precise pathogenesis is not well understood. Cytokines are thought to be involved in the inflammation of islet β-cells in diabetes; however, few studies have investigated this hypothesis in NODAT. A total of 309 kidney transplant recipients (KTRs) were included in this study. An association between kidney transplants, and the development of diabetes after transplant (NODAT) was investigated. Comparison was made between KTRs who develop diabetes (NODAT cases) or did not develop diabetes (control), using key cytokines, IL-6 G (− 174)C, macrophage mediator; IL-4 C (− 490)T, T helper (Th)-2 cytokine profile initiator; Th-1 cytokine profile initiator interferon-γ T (+ 874) A gene and TGF β1 C (+ 869) T gene polymorphisms were investigated. The genes were amplified using well-established polymerase chain reaction (PCR) techniques in our laboratory. Compared to the AA and AT genotypes of interferon gamma (IFNG), there was a strong association between the TT genotype of IFNG and NODAT kidney transplant recipients (KTRs) versus non-NODAT KTRs (p = 0.005). The AA genotype of IFNG was found to be predominant in the control group (p = 0.004). Also, significant variations of IL6 G (− 174) C, IL-4 C (− 590) T, interferon-γ T (+ 874) A gene and transforming growth factor β1 C (+ 869) T may contribute to NODAT. Our data is consistent with theTh-1/T-reg pathway of immunity. Further larger pan Arab studies are required to confirm our findings.
Highlights
Genetic predisposition to New Onset Diabetes After Transplantation (NODAT) likely involves an inherited defect in the peripheral tolerance to T-cell infiltration along with inadequate insulin secretion[14,15,16]
It is well established that the IFN-γ gene polymorphism T (+ 874) A (IFNG) of the first intron is correlated with serum level of IFN-γ production and mRNA expression in vitro and in vivo; the TT genotype correlates with high levels of IFN-γ production, and TA and AA are correlated with intermediate and low production level[18,22,34,35,36,37,38]
Our results indicate that susceptibility to NODAT might be monitored by genotyping kidney transplant recipients (KTRs) who developed diabetes compared with KTRs who did not develop diabetes for selected major T helper (Th) 1(IFNG)/ Th-2 (IL-4)/TGFB, T-reg in addition to IL-6, macrophage derived cytokines
Summary
Genetic predisposition to NODAT likely involves an inherited defect in the peripheral tolerance to T-cell infiltration along with inadequate insulin secretion[14,15,16]. It is well established that the IFN-γ gene polymorphism T (+ 874) A (IFNG) of the first intron is correlated with serum level of IFN-γ production and mRNA expression in vitro and in vivo; the TT genotype correlates with high levels of IFN-γ production, and TA and AA are correlated with intermediate and low production level[18,22,34,35,36,37,38]. This polymorphism coincides with a putative NF-κB binding site that may mediate high production of IFN-γ39,40. The same is true for IL-4 C (− 590) C for low levels, and TC for putative intermediate protein levels[22,50]
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