“ATG16 L1 a Additional Risk Factor for TRM After allogeneic Stem Cell Transplantation”.
Authors: Landfried Karin , Hausmann Martin , Rogler Gerhard , Wolff Daniel , Dickinson Anne M , Collin Matthew , Finke Juergen , Holler Ernst , Andreesen Reinhard 
Published: October 2019

Abstract
Abstract 1155
Poster Board I-177

Introduction
A genome wide association scan of DNA polymorphisms identified association of a threonine-to-alanine substitution (T300A) in the autophagy-related 16-like gene ATG16 L1 as a new genetic risk factor of Crohn's disease. As our group had previously reported SNPs of another innate immunity receptor important in Crohn's disease, NOD2/CARD15, as a risk factor of severe graft-versus-host disease (GvHD) and treatment related mortality (TRM) following allogeneic stem cell transplantation (SCT), we now assessed the role of ATG16L in complications following SCT.

Material and Methods
A total of 127 HLAidentical sibling donor/recipient pairs were included. DNA from donors and recipients were analyzed for the ATG16L1 polymorphism and presence or absence of NOD2/CARD15 variants as previously published. Results of ATG16L1 and NOD2/CARD15 were correlated with clinical characteristics and outcome data, which were documented in a SPSS 17 database. The role of polymorphisms in GvHD III/IV was assessed by cross tabs, treatment related mortality (TRM) and overall survival were assessed by Kaplan Meier analysis. All patients and donors gave informed consent to analysis of genetic risk factors of GvHD.

Results
In 15 (12%) both recipient and donor were wildtype ATG16L1, in 25 (19%) either donor or recipient had the variant; and in 87 (69%) both donor and recipient had the variant. In 34 pairs, additional NOD2/CARD15 SNPs were observed.
Severe GvHD occured in 6%, if both donor and recipient were ATG16L1 wildtype but increased to 22% if donor or recipient had the variant. Treatment related mortality increased in the presence of a donor variant (16% versus 46%, p 0.03) or if both; recipient and donor had variants (21% vs 48%, p 0.03). There seemed to be a gene dose effect for TRM, which was 13% if both were wildtype, 27% in the presence of either a donor or recipeint varaint and 48% if both had the variant (p≤ 0.05). Overall survival was not significantly different between these groups. In multivariate analysis, presence of ATG16L1 variant in both, donor and recipient was an independent risk factor for treatment related mortality when compared with age and stage of underlying disease (Hazard ratio 2.5, 95% confidence interval 1.1 – 6.1). Additional presence of NOD2/CARD15 variants seemed to be additive: TRM rose from 36% in recipients with ATG16L1 variant to 59% in the presence of additional recipient NOD2/CARD15 variants and from 34% in donors with ATG16L1 variants to 64%, if donors had additional NOD2/CARD15 SNPs.

Conclusions
As reported ATG16L1 polymorphism is a genetic risk factor for inflammatory bowel disease. In our work ATG16L1 polymorphism seems also to contribute to increased TRM in patients receiving allogeneic SCT. An accurate analysis of the causes of death is still accomplished. Altogether the data underline the role of the innate immunity and the disturbed antibacterial defense in the pathophysiology of transplant-associated complications.

Disclosures
No relevant conflicts of interest to declare.