Distribution of KIR2DS4 Alleles in Chinese Han Population and the Impact of KIR2DS4 Alleles On the Development of Acute Gvhd Post Unrelated Allogeneic Hematopoietic Stem Cell Transplantation.

Abstract 4496

The Killer cell immunoglobulin-like receptors (KIRs) are a diverse family of receptors on natural killer (NK) cells and play a role in hematopoietic stem cell transplantation (HSCT). KIR2DS4 gene is the most diverse stimulatory KIR loci and the only activating gene in haplotype A. The KIR2DS4 deleted variant differs from the normal KIR2DS4 sequence by a 22 bp deletion in exon 5, which causes a frame shift, yielding a truncated KIR2DS4 protein with loss of the transmembrane and cytoplasmic domains of the full-length KIR2DS4 protein. The deleted variant of KIR2DS4 is not anchored to the cell membrane but encodes a soluble form of the protein that is potentially secreted. To obtain the frequencies of 2DS4 allele in the Chinese-Han population and the impact of KR2DS4 alleles on the clinical outcomes of HSCT, a sequence based testing (SBT) and TOPO TA cloning system identifying and distinguishing alleles of the KIR2DS4 gene has been established. The method was applied to a total of 150 Chinese-Han individuals: 75 patients who received T-depleted HSCT to treat leukemia and their unrelated donors (URD). All patients were undergoing transplantation for CML (n=24), AML (n=19), ALL (n=29) and other malignancies (n=3). The majority (139) of the 150 samples (92.7%) were positive for KIR2DS4. Sequencing of most of the coding region of this gene identified four of the eight known KIR2DS4 alleles, KIR2DS4*00101, *003,*004, and *007.The KIR2DS4 deleted variant was found in 47.5% individuals. The ratio of deleted to non-deleted versions of KIR2DS4 was approximately 1:2 within this Chinese-Han population. Three KIR2DS4 novel alleles were identified. 44% individuals carried two group A haplotypes. The overall survival rates was lower in transplants where the donors carried two 2DS4 full-length allele (2DS4*001) in comparison with those where the donors carried less (0 or 1) 2DS4*001 allele (P=0.031). In transplantations where donors carried KIR2DS4-full length, the aGVHD rate was 42.9% (6 of 14). In contrast, if the donors carried only KIR2DS4-deletion or both 2DS4 deletion and full length alleles, the aGVHD rate was 4.8 % (1 of 21). Upon statistical analysis, 2DS4-full length donors had a significantly increased rate of aGVHD in URD transplantations (RR 9.0 [95% CI 1.2-66.9], P=0.01). These results demonstrated that Chinese Han population is distinct in 2DS4 allele frequencies in comparison to some other populations. The expression of the full length KIR2DS4 may increase the risk of aGVHD and contribute to a worse clinical outcome after URD-HSCT. These data would be beneficial for the selection of suitable donors. Moreover, our findings suggest that KIR genotyping, in addition to HLA typing, should be performed for prospective donors to improve the outcome of transplantation.