The Distribution of KIR Gene in Chinese Population and the Effect of Donor KIR and Patient HLA Genotypes on Outcome Following Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Huang He , Wu Gongqiang , Lai Xiaoyu , Tan Yamin , Luo Yi , Zhu Faming 
Published: April 2020

Killer cell immunoglobulin-like receptors (KIR) are a family of inhibitory and activatory receptors and are expressed by most NK cells. The interaction between KIR and human leukocyte antigen (HLA) molecules expressed on target cells is known to modulate the cytolytic activity of NK cells. At present, seventeen KIR genes have been identified, and the number of KIR gene loci has been reported to vary among individuals, resulting in a heterogeneous array of KIR genes in different populations. KIR haplotypes are divided into two distinctive groups based on their gene contents. Ruggeri, et al, first reported that KIR-ligand mismatch can alleviate aGVHD, reduce relapse and improve disease-free survival in mismatched hematopoietic stem cell transplants, while some studies show that this kind of mismatch is deleterious. Now the effect of NK cells alloreactivity on outcome of hematopoietic stem cell transplantation remains controversial. Our study is to analyze the KIR gene contents and investigate the impact of KIR-ligand mismatch on outcome following hematopoietic stem cell transplantation in Chinese population.

METHODS: 203 cases of allogeneic hematopoietic stem cell transplantation between Jan. 2001 to May. 2008 were involved in the study. KIR genes were typed by using PCR-SSP, and HLA-A, -B and -C loci genes were used by PCR-SSP or PCR-SSO technology. KIR-ligand incompatibility were assessed based on HLA-Cw (divided into C1 and C2 group) and three major inhibiting KIR genotypes (KIR2DL1, KIR2DL2 and KIR2DL3) of 203 donor/recipient pairs. These patients received myeloablative (n=180) or nonmyeloablative (n=23, with ATG) conditioning followed by hematopoietic stem cell transplantation from HLA matched (n=164) or mismatched (n=39) donors. All patients received mycophenolate mofetil (MMF) combined with CsA and short course MTX regimen as prophylaxis for aGVHD.

RESULTS: All seventeen KIR genes were observed in the Chinese population. Framework genes KIR3DL3, KIR3DP1, KIR2DL4 and KIR3DL2 were present in all individuals. The most frequent non-framework KIR genes were: KIR2DL1 (99.5%), KIR3DL1 (97.0%), KIR 2DS4 (97.5%), KIR2DL3 (99.5%) and KIR2DP1 (99.5%). The other gene frequencies were KIR2DS2 (25.1%), KIR2DL2 (25.6%), KIR2DL5A (32.5%), KIR2DL5B (30.0%), KIR2DS5 (23.6%), KIR2DS1 (43.8%), KIR2DS3 (21.2%) and KIR3DS1 (34.0%). The most prevalent haplotype group found in the population was A haplotype. Group A haplotypes outnumbered group B haplotypes in frequency by approximately 3:1, with individuals having two group A haplotypes accounting for 48.8% (99/203). HLA genotyping showed that 156 out of 203 (76.8%) donor-recipient pairs could be characterized by lack of recipient HLA-Cw ligand for donor KIR2DL1, KIR2DL2/2DL3. KIR-ligand mismatch was not associated with any deleterious or beneficial influence on relapse or overall survival (OS) in Chinese population with hematopoietic stem cell transplantation. But KIR-ligand mismatch could lead to a decreased incidence of aGVHD (36.1% vs 56.3%, P=0.018). When donor NK cells had KIR2DS2 gene, the recipient acquired a decreased incidence of aGVHD (13.2% vs 49.3%, P&lt;0.001), and had better OS (20.8% vs 34.7%, P=0.041). We also found that the presence of donor KIR2DS5 have a positive effect on aGVHD (25.0% vs 44.5%, P=0.011), however, it didn’t improve OS (27.1% vs 32.9%, P=0.197). There was almost no effect on relapse rate even if donor expressed KIR2DS2 or KIR2DS5.

CONCLUSION: Our data demonstrated that Chinese population was distinct in KIR gene frequencies and putative KIR haplotypes in comparison to some other populations. KIR-HLA mismatch was not any better effect on relapse, OS, but it had a better effect on aGVHD. Donors with gene KIR2DS2 or KIR2DS5 were associated with lower incidence of aGVHD in allogeneic hematopoietic stem cell transplantation.