Prognostic significance of NOD2/CARD15 variants in HLA-identical sibling hematopoietic stem cell transplantation: Effect on long term outcome is confirmed in 2 independent cohorts and may be modulated by the type of gastrointestinal decontamination Running head: NOD2/CARD15 in HLA-identical sibling HSCT

In order to assess the role of NOD2/CARD15 variants on the long term outcome of allogeneic stem cell transplantation in a genetically homogenous group, we extended our previous study (cohort I, n=78) and typed DNA from additional 225 recipients and their HLA-identical sibling donors (cohort II) from 4 European centres for NOD2/CARD15 SNPs. Results of genotyping were compared with clinical outcome: The strong association of NOD2/CARD15 variants with transplant related mortality (TRM) was confirmed in univariate and multivariate analysis: TRM increased from 20% in cohort I/ 22% in cohort II in recipient/donor pairs without any NOD2/CARD15 variants to 47% (cohort I)/ 32% (cohort II) in the presence of 1 variant in either donor or recipient and further to 57% (cohort I) / 74% (cohort II) in the presence of 2 or more variants (p 0.002 in both cohorts). NOD2/CARD15 SNPs were not associated with relapse rate but had a strong impact on overall survival. In an analysis of centre effects, the type of gastrointestinal decontamination was the only factor interfering with the prognostic significance of NOD2/CARD15 SNPs. Our data further support an interaction between gastrointestinal defense mechanisms, activation of the innate immune system and specific transplant related complications. For personal use only. on October 31, 2017. by guest www.bloodjournal.org From