NOD2 Polymorphisms and Their Impact on Haematopoietic Stem Cell Transplant Outcome

Abstract

Haematopoietic stem cell transplantation (HSCT) is a valuable tool in the treatment of many haematological disorders. Advances in understanding HLA matching have improved prognoses. However, many recipients of well-matched HSCT develop posttransplant complications, and survival is far from absolute. The pursuit of novel genetic factors that may impact on HSCT outcome has resulted in the publication of many articles on a multitude of genes. Three NOD2 polymorphisms, identified as disease-associated variants in Crohn's disease, have recently been suggested as important candidate gene markers in the outcome of HSCT. It was originally postulated that as the clinical manifestation of inflammatory responses characteristic of several post-transplant complications was of notable similarity to those seen in Crohn's disease, it was possible that they shared a common cause. Since the publication of this first paper, numerous studies have attempted to replicate the results in different transplant settings. The data has varied considerably between studies, and as yet no consensus on the impact of NOD2 SNPs on HSCT outcome has been achieved. Here, we will review the existing literature, summarise current theories as to why the data differs, and suggest possible mechanisms by which the SNPs affect HSCT outcome.

Distinct NOD2 polymorphism status is associated with differential outcome in hematopoietic stem cell transplantation: results from a meta-analysis

“…Our strategy was to use meta-analysis due to its statistical power in order to potentially reduce between-study heterogeneity in the characteristics of transplant pairs, differential immunosuppressive protocols and transplant techniques that may obscure a real susceptibility to GvHD [3] . Our study, taken together with all currently available published data, indicates that HSCT patients with NOD2 SNPs on the donor side appear to be associated with an increased risk of severe GvHD.…”

“…It is possible that the NOD2 gene plays different roles in the development of GvHD. For example, NOD2 variants may contribute to the onset of GvHD to varying degrees by interrupting the so-called cytokine storm that is necessary for initiating the syndrome [3] . The disruption of the cytokine storm at an early stage posttransplantion would result in the absence of a GvHD response [21] .…”

“…The NOD2 gene is located in humans on chromosome 16 (16q21). It has a C-terminal leucine-rich repeat region for sensing microbial products, a central nucleotide-binding domain (NACHT), and an N-terminal CARD (caspase activation and recruitment domain) [3] . In antigen-presenting cells, NOD2 expression leads to downstream activation of innate pathways of host defense [4] when triggered by its interaction with Muramyl Dipeptide (MDP), a component of gram-positive and -negative bacterial cell walls, subsequently leading to the activation of the pro-inflammatory NF-κB pathway.…”

“…Although SNPs 8,12, and 13 are thought to reduce the ability of MDP to activate NOD2 and consequently the activation of NF-κB, resulting in reduction in the production of cytokines and antimicrobial peptides, these loss-of-function effects caused by the SNPs initially proved controversial, as an enhanced cytokine response is characteristic of GvHD. Naturally, other studies have yielded inconsistent results [8,9] , possibly due to limited sample size, differences in genetic background within a transplant pair, and variable study designs [3,10,11] . Here, a comprehensive search and meta-analysis were used for the first time to confirm the association of differential NOD2 polymorphism status in Caucasian ethnic populations with HSCT outcome.…”

Can determination of gene polymorphism be of practical value in tailoring the treatment of HSCT patients?

“…Clinical observation of SNPs in the NOD2/CARD15 gene suggests that single-nucleotide polymorphism (SNP) 13 impairs the natural immunity mechanism, but not the one leading to cytokine production. 5 This observation helps in understanding the mechanism of frequently fatal septic complications seen in patients with SNP 13. The results of the abovementioned observations show that the effect of the above-quoted gene polymorphisms may be clinically seen only in situations associated with a higher risk of infections.…”