DAAM2 Polymorphism and Allogeneic Hematopoietic Stem Cell Transplantation.

Background WNT signaling pathway is known to have important functions in embryogenesis, cellular proliferation and regeneration, stem cell renewal and oncogenesis. DAAM2 is one of the key protein of WNT/PCP signaling pathway. This study examines the association of DAAM2 polymorphism and the clinical outcomes in patients treated with allogeneic hematopoietic stem cell transplantation (HSCT). Objectives and methods Candidate SNPs associated with acute graft versus host disease (GVHD) were selected using DNA chip analysis with Illumina Infinium Human-1 microarrays™ in 15 patients who treated with allogeneic HSCT for various hematologic and oncologic diseases with or without acute GVHD. Six SNPs (rs2504787, rs2504086, rs2504082, rs3004067, rs882559, and rs3004070) on DAAM2 were proven to be associated with acute GVHD, and extended genotyping was executed by Taqman™ protocol in more large population of 239 patients in single institute. Retrospective analysis for medical records was performed to define correlation of these SNPs with clinical outcomes of the patients. Results rs882559 located upstream from exon 24, was proven to be associated with acute GVHD incidence. Acute GVHD incidence was significantly lower in the patients with CC genotype of rs882559 than those with CG or GG genotype (HR 0.466, 95% CI 0.224∼0.969, p=0.0409). The allele frequency of C was 55% and that of G 44%. The genotyping disclosed CC in 77, CG in 110, and GG in 52. Multivariate analyses on various parameters including sex, age, transplant method (reduced intensity conditioning vs. conventional conditioning), stem cell source, risk group, and DAAM2 genotypes, as parameters, identified high-risk group defined in our previous study (KH Lee et al., Haematologica, 2007;92 ; HR 2.41, 95% CI 1.47∼3.94, p<0.001), age over 50 years (HR 1.70, 95% CI 1.18∼2.45, p=0.004) and codominant genotype of rs2504082, i.e., an intron mutation upsteam from exon 15 (HR 1.326, 95% CI 1.02∼1073, p=0.0378) as risk factors for a shorter survival. Interpretation and conclusions This is the first clinical study for the DAAM2 polymorphism, furthermore, and its association with clinical outcomes of allogeneic HSCT. The role of rs882559 and rs2504082 were not identified by now, but its mutation might affect to the transcription of following coding genes causing the changes of its functions. This study suggested the clinical value of DAAM2 polymorphism as a predictive parameter of clinical outcomes of allogeneic HSCT, and its importance in WNT signaling pathway.