| [Purpose]To examine the diversity of KIR haplotypes via inheritance from parents to child, and characterize the distribution of KIR genotypes/haplotypes, centromeric/telomeric motifs in a Chinese Han population that included family members and unrelated individuals. On this basis, to investigate the influence of donor KIR haplotypes and cen/tel gene motifs on the outcomes of URD- hematopoietic stem cell transplantation(HSCT).[Methods](1) We performed Killer cell immunoglobulin-like receptor(KIR) genotyping on 1271 individuals of Chinese Han origin including 102 families and 965 unrelated individuals. The families(with one child and both parents) were subjected for haplotype analysis.(2) A total of 210 Chinese patients who underwent URD-HSCT in First Affiliated Hospital of Soochow University were investigated. We performed KIR and HLA genotyping for the 210 donor and recipient pairs with 4-year follow-up monitoring.[Results](1) Since the child and the parents are related, only the data of the 204 parents(2n = 408 chromosomes) were used for frequency calculation. The family study showed segregation of one A haplotype and at least 15 unique B haplotypes. The most commonly observed haplotypes in group B were B1, B2, and B3, present at a frequency of 10.05%, 6.62%, and 4.90%, respectively.Knowing the haplotypes that each individual carried, we were able to determine that 53.92%(110 of 204) individuals were AA, 35.29%(72 of 204) were AB, and 10.78%(22 of 204) were BB. For the 22 individuals who were homozygous for group B haplotypes, 8 individuals who had been previously assigned with genotype Bx according to their gene contents should be actually referred to as BB after haplotype analysis. The gene combinations of group A and B1/B2/B3 haplotype were the most frequent genotypes named as Bx1, Bx2, and Bx3, present at a frequency of 13.72%, 7.35%, and 4.41% in the family panel, and at a frequency of 15.86%, 10.15%, and 5.80% in the unrelated panel, respectively.On the basis of the combination of KIR genes, six centromeric and seven telomeric gene motifs have been identified. We confirmed the presence of three centromere motifs and two telomere motifs previously reported. Three additional centromere motifs and five telomere motifs were observed in the studied population. Haplotype A specific KIR gene motifs c A01 and t A01 were carried by majority of individuals. Motif c B02 was the most frequent haplotype B specific centromeric segment while t B01 was the most frequent haplotype B specific telomeric segment. The combination of c A01 and t A01 was the most frequent KIR haplotype in the studied population. In group B, the combinations of c A01 & t B01 and c B02 & t A01 were the most frequent B specific haplotypes.Estimates for the LD values and two locus haplotype frequencies determined between each pair of the 14 KIR specificities. The most significant positive associations were observed in the following pairs of KIR specificities: 2DL1/2DL3, 2DS1/2DL5 A, 2DL2/2DS2, 2DL5A/3DS1, 2DS1/3DS1, 2DL1/2DP1, and 2DL3/2DP1. The most significant negative associations were observed in the following pairs of KIR specificities: 2DL5A/2DS4 F, 2DS1/2DS4 F, 2DS4F/2DS4 D, 2DS5/3DL1, and 2DS4F/3DS1.(P<0.05)(2) Donor KIR genotype Bx was associated with a significantly improved 4-year OS for AML/MDS patients [hazard ratio(HR): 0.443; 95% confidence interval(CI), 0.216–0.909; P = 0.026], RFS(HR: 0.430; 95% CI: 0.210–0.880; P = 0.021), and reduced NRM(HR, 0.342; 95% CI, 0.142–0.824; P = 0.017). However, the benefit of donor KIR genotype Bx was not observed in all patients. Division of Bx donors into Bx1(Cen-A/A; with 2DS5 on the telomere), Bx2(Cen-A/A; with 2DS3 on the telomere), Bx3+Bx4(Cen-A/B), and other Bx groups indicated that donor KIR profile Bx1 was a risk factor for lower OS(P = 0.047) and RFS(P = 0.041). Considering the patients’ disease status at transplantation, a higher survival rate was observed for transplants from Bx2, Bx3, and Bx4 donors compared to Bx1 donors for patients at standard risk(CR1, n = 82; OS: P = 0.024; RFS: P = 0.021). The P value of OS and RFS between Bx1(n = 7) group and other Bx group(n = 26) for HLA-matched AML/MDS transplants at standard risk was 0.019(3/7 vs. 2/26) and 0.024, respectively. However, no statistically significant difference was observed in patients of the high-risk group(CR2 and CR3, n = 40; OS: P = 0.887; RFS: P = 0.812).Donors with cen-B were associated with a significantly improved 4-year OS in AML/MDS patients(HR, 0.397; 95% CI, 0.170–0.931; P = 0.034), RFS(HR,.395; 95% CI, 0.169–0.923; P = 0.032), and reduced NRM(HR, 0.273; 95% CI, 0.096–0.779; P = 0.015). No effect on a Gv HD, c Gv HD, and relapse was observed. Considering the HLA matching status, the positive effect of cen-B in OS(1/21 vs. 22/68; HR, 0.334; 95% CI, 0.129–0.862; P = 0.023), RFS(HR, 0.332; 95% CI, 0.129–0.856; P = 0.022) and NRM(HR, 0.265; 95% CI, 0.081–0.862; P = 0.027) was also observed in HLA-matched transplants for AML/MDS patients(n = 89). In the standard-risk group(CR1), donors with cen-B were associated with significantly improved 4-year OS(HR, 0.256; 95% CI, 0.084–0.774; P = 0.016) and RFS(HR, 0.252; 95% CI, 0.084–0.758; P = 0.014), and reduced NRM(HR, 0.273; 95% CI, 0.096–0.779; P = 0.015) There was also no statistical difference for ALL/NHL and CML patients. However, this particular effect did not increase with a higher number of Cen-B motifs(c B/B vs. c A/B; OS: P = 0.755; RFS: P = 0.768). No effect was also observed on high-risk AML/MDS, ALL/NHL, and CML patients.[Conclusion]Overall, this study showed the diversity of KIR haplotypes and genotypes in the population and developed a criterion for distinguish KIR haplotypes. KIR genotyping and haplotype analysis should be useful for selection of the most optimum donor grafts with favorable KIR gene content for transplants. Also it may benefit in providing theoretical and practical basis to perform donor specific NK-mediated individualized treatment and thus improving the clinical outcomes. |
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