NK cell function is controlled by the cell expression of killer immunoglobulin-like receptors (KIRs) and their ligation with the corresponding HLA ligands. Various malignancies have been associated with certain KIRs surface cell expression and various KIR/HLA ligand combinations. Prior research using case/control study design demonstrates the role of KIR and KIR HLA ligands as genetic factor involved in tumor susceptibility. The objective of this study was to investigate the family-based association of KIRs, HLA class I ligands and KIR/ligand combinations with leukemia diagnosis in families having a leukemia diagnosed child. Sixty-seven families that met the index leukemia case criteria (acute lymphoblastic leukemia, ALL, n = 45; acute myeloid leukemia, AML, n = 13; chronic myeloid leukemia, CML, n = 9; first degree healthy relatives n = 159) were examined. Our study consisted of two phases. In Phase1 case-control study, we primarily compared patients to their healthy siblings to asses if a marker or genotype may be associated with leukemia, excluding the impact of the environment. Phase 2 consisted of a secondary family-based association study. KIR genotyping was performed by PCR-SSP method. KIR HLA ligands were defined by direct method using PCR-SSP method and/or indirect base on high resolution typing of HLA-A, -B, -C alleles. Results of phase 1 showed an increase in the frequency of KIR genotype (with a ratio = 0.57; higher frequency for inhibitory KIRs vs. activating KIRs) among leukemia patients compared to healthy siblings. Results of the phase 2 familial study observed an association between HLA-C1+/BBw4+/ABw4+ haplotype (a mediator of inhibitory signals) and leukemia. Also, we concluded that the absence of HLA-ABw4 alleles was related to leukemia development.
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2. Mandelboim O Reyburn H Vales-Gomez M et al. Protection from lysis by natural killer cells of group 1 and 2 specificity is mediated by residue 80 in human histocompatibility leukocyte antigen C alleles and also occurs with empty major histocompatibility complex molecules. J Exp Med 1996 184 913-922.
3. Collona M Samaridis S. Cloning of immunoglobulin-super-family members associated with HLA-C and HLA-B recognition by human natural killer cells. Science 1995 268: 405-408.
4. Foley B De Santis D Van Beelen E et al. The reactivity of Bw4+ HLA-B and HLA-A alleles with KIR3DL1:implications for patient and donor suitability for haploidentical stem cell rans-plantations. Blood 2008 112 435-443.
5. Gumperz J Litwin V Philips J et al. The Bw4 public epitope of HLA-B molecules confers reactivity with natural killer cell clones that express NKB1 a putative HLA receptor. J Exp Med 1995; 181 1133-1144.
6. Hansasuta P Dong T Thananchi H et al. Recognition of HLAA3 and HLA-A11 by KIR3DL2 is peptide-specific. Eur J Immunol 2004 34 1673-1679.
7. Biassoni R Pessino A Malaspina A et al. Role of amino acid position 70 in the binding affinity of p50.1 and p58.1 receptors for HLA-Cw4 molecules. Eur J Immunol 1997 27 3095-3099.
8. Stewart C Laugier-Anfossi F Vely F et al. Recognition of peptide-MHC class I complexes by activating killer immunoglobulin-like receptors. Proc Natl Acad Sci USA 2005 102 13224-13229.
9. Single R Martin MP Gao X et al. Global diversity and evidence for coevolution of KIR and HLA. Nat Genet 2007 39 1114-1119.
10. Alter G Martin MP Teigen N et al. Differential natural killer cell-mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes. J Exp Med 2007 204 3027-3036.
11. Khakoo SI Carrington M. KIR and disease: a model system or system of models. Immunol Rev 2006 214 186-201.
12. Karabon L Jedynak A Giebel S et al. KIR/HLA gene combinations influence susceptibility to B-cell chronic lymphocytic leukemia and the clinical course of disease. Tissue Antigens 2011 78 129-138.
13. Besson C Roetync S Williams F et al. Association of killer cell immunoglobulin-like receptor genes with Hodgkin lymphoma in a familial study. PLoS ONE 2007 2(5) e406.
14. Shahsavar F Tajik N Entezami K et al. KIR2DS3 is associated with protection against acute myeloid leukemia. Iran J Immunol 2010 7 8-17.
15. Verheyden S Demanet C. Susceptibility to myeloid and lymphoid leukemia is mediated by distinct inhibitory KIR-HLA ligand interactions. Leukemia 2006 20 1437-1438.
16. Pamuk GE Tozkir H Uyanik MS et al. Natural killer cell killer immunoglobulin-like gene receptor polymorphisms in non-Hodgkin lymphoma: possible association with clinical course. Leuk Lymphoma 2015 56(10) 2902-7.
17. Sullivan EM Jeha S Kang G et al. NK cell genotype and phenotype at diagnosis of acute lymphoblastic leukemia correlate with postinduction residual disease. Clin Cancer Res 2014 20(23) 5986-94.
18. Misra MK Prakash S Moulik NR et al. Genetic associations of killer immunoglobulin like receptors and class I human leukocyte antigens on childhood acute lymphoblastic leukemia among north Indians. Hum Immunol 2016 77(1) 41-6.
19. Sugioka DK Gonçalves CE Bicalho MD. KIR repertory in patients with hematopoietic diseases and healthy family members. BMC Hematology 2016 16 25.
21. Varbanova V Mihaylova A Naumova E. Olerup SSP KIR HLA ligand typing Kit. A new opportunity for KIR ligand assignment in clinical settings. C R Acad Bulg Sci 2010 63(5) 713-722.
22. Gonzalez-Galarza F Christmas S Middleton D Jones A. Allele frequency net: a database and online repository for immune gene frequencies in worldwide populations. Nucleic Acids Research 2011 39 D913-D919.
23. Spielman RS McGinnis RE Ewens WJ. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993 52: 506-516.
24. Wall J Pritchard J. Haplotypes blocks and linkage disequilibrium in the human genome. Nat Rev Genet 2003 4 587-597.
25. Knapp M. The transmission/disequilibrium test and parental-genotype reconstruction: the reconstruction-combined transmission/disequilibrium test. Am J Hum Genet 1999 64 861-870.
26. Spielman RS Ewens WJ. A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. Am J Hum Genet 1998 62 450-458.
27. Horvath S Xu X Laird NM. The family based association test method: strategies for studying general genotype–phenotype associations. Eur J Hum Genet 2001 9 301-306.
28. Faure M Longo E. KIR2DL4 (CD158d) an NK cell-activating receptor with inhibitory potential. J Immunol 2002 168 6208-14.
29. Kikuchi-Maki A Yusa S Catina T Cambpbell K. KIR2DL4 is an IL-2 regulated NK cells receptor that exhibits limited expression in humans but triggers strong IFN-gamma production. J Immunol 2003 171 3415-3425.
30. Hsu K Chida S Geraghty D and Dupont B. The killer cell immunoglobulin-like receptor (KIR) genomic region: gene-order haplotypes and allelic polymorphism. Immunological Reviews 2002 190 40-52.