Review of Genetic Variation as a Predictive Biomarker for Chronic Graft-Versus-Host-Disease After Allogeneic Stem Cell Transplantation

Abstract

Chronic graft-versus-host disease (cGvHD) is one of the major complications of allogeneic stem cell transplantation (HSCT). cGvHD is an autoimmune-like disorder affecting multiple organs and involves a dermatological rash, tissue inflammation and fibrosis. The incidence of cGvHD has been reported to be as high as 30% to 60% and there are currently no reliable tools for predicting the occurrence of cGvHD. There is therefore an important unmet clinical need for predictive biomarkers. The present review summarizes the state of the art for genetic variation as a predictive biomarker for cGvHD. We discuss three different modes of action for genetic variation in transplantation: genetic associations, genetic matching, and pharmacogenetics. The results indicate that currently, there are no genetic polymorphisms or genetic tools that can be reliably used as validated biomarkers for predicting cGvHD. A number of recommendations for future studies can be drawn. The majority of studies to date have been under-powered and included too few patients and genetic markers. Like in all complex multifactorial diseases, large collaborative genome-level studies are now needed to achieve reliable and unbiased results. Some of the candidate genes, in particular, CTLA4, HSPE, IL1R1, CCR6, FGFR1OP, and IL10, and some non-HLA variants in the HLA gene region have been replicated to be associated with cGvHD risk in independent studies. These associations should now be confirmed in large well-characterized cohorts with fine mapping. Some patients develop cGvHD despite very extensive immunosuppression and other treatments, indicating that the current therapeutic regimens may not always be effective enough. Hence, more studies on pharmacogenetics are also required. Moreover, all of these studies should be adjusted for diagnostic and clinical features of cGvHD. We conclude that future studies should focus on modern genome-level tools, such as machine learning, polygenic risk scores and genome-wide association study-transcription meta-analyses, instead of focusing on just single variants. The risk of cGvHD may be related to the summary level of immunogenetic differences, or whole genome histocompatibility between each donor-recipient pair. As the number of genome-wide analyses in HSCT is increasing, we are approaching an era where there will be sufficient data to incorporate these approaches in the near future.

Keywords: biomarkers; gene marker; genetic screen; graft versus host disease (GvHD); stem cell transplantation (HSCT).