Vojvodić S, Ademović-Sazdanić D.

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Vojvodić S, Ademović-Sazdanić D. A case report of KIR haplotype analysis in one family lacking KIR 2DL1-2DP1 genes Vojvodić S, Ademović-Sazdanić D. Institute for Blood Transfuson of Vojvodina, Tissue Typing Compartment, Novi Sad, Serbia

Klinical importance of KIR genes in HSCT KIRs are encoded by genes located in the chromosomal region 19q13.4 within the leukocyte receptor complex (LRC). KIR gene cluster exhibits extensive allelic and haplotypic diversity Belong to non-HLA genes of great importance in HSCT KIR/HLA missing ligand status is assocated with strong GvL/T effect and therefore with enhanced overall survival, decreased disease relapse, and increased probability of disease-free survival B KIR haplotypes contribute to relapse protection and improved survival(Cen-B homozygosity ) Imperative in donor search strategy

Donor search strategy in our Institute Since 2010. HLA A,B,C,DRB1,DQB1 PCR SSP low resolution genotyping of recipents and related donors KIR PCR SSP low resolution genotyping ABO/RHD/RHCE/KKD/MNS low resoution genotyping, CDC-AHG CM, Ab screening/identification by CDC,ELISA KIR/HLA missmatches Recipient HLA C1/C1 genotype Donor A and/or B KIR haplotypes Donor KIR B group content (IPD-KIR Database) In 2012. we started with PCR SSOP HLA/KIR low resolution typing (Luminex) –unrelated HSCT donors

KIR/HLA missmatches INHIBITORY KIR KIR LIGAND KIR2DL1 HLA-C group 2 (02, 04, 05, 06, 15, 1602, 17,18) KIR2DL2/3 HLA-C group 1 (01, 03, 07, 08, 12, 13, 14,1601/4) KIR3DL1 HLABw4 (B*27,A*23,A*24,A*25,A*32) KIR3DL2 HLA A*03,A*11 DONOR RECIPIENT Farag S. S. et al. Blood 2002; 100: 1935-1947.

KIR A and B haplotypes KIR GENES HAPLOTYPE A HAPLOTYPE B KIR2DL1 “FRAMEWORK“GENES HAPLOTYPE B KIR2DL1 KIR2DL3 KIR2DS4 KIR3DL1 KIR2DL4 KIR3DL2 KIR3DL3 KIR3DP1 KIR2DS1/2/3/5 KIR3DS1 KIR2DL5 (A/B) KIR2DL2

Group A and B KIR haplotypes centromeric (Cen) and telomeric (Tel) gene-content motifs KIR3DL3-KIR2DL3-KIR2DP1-KIR2DL1-KIR3DP1 Cen-B1 KIR3DL3-KIR2DS2-KIR2DL2-KIR2DL5B-KIR2DS3 (or KIR2DS5)- KIR2DP1-KIR2DL1-KIR3DP1 Cen-B2 KIR3DL3-KIR2DS2-KIR2DL2-KIR3DP1 Tel-A1 KIR2DL4-KIR3DL1-KIR2DS4-KIR3DL2 Tel-B1 KIR2DL4-KIR3DS1-KIR2DL5A-KIR2DS3 (or KIR2DS5)-KIR2DS1-KIR3DL2 Hou L. et al. Genes and Immunity 2012;13:47-58

KIR and HLA alleles i parents Mother(M.Z.): KIR: 2DL2; 2DL4(norm and del); 2DS2; 2DS4(del-22bp);3DL1;3DL2;3DL3;3DP1 HLA:A*24,*32; B*08,*27; C*02,*07; DRB1*03,*16; DQB1*02,05;  Father (M.A.): KIR: 2DL2;2DL4(norm);2DL5;2DS1;2DS2; 2DS5;3DL2;3DL3;3DS1;3DP1 HLA:A*02,*32; B*27,*41; C*02,*07; DRB1*03,*16; DQB1*02,*05;

KIR and HLA alleles in offsprings  Patient (M.M.): KIR: 2DL2; 2DL4(del); 2DL5; 2DS1; 2DS2;2DS4(del-22bp); 2DS5; 3DL1;3DL2;3DL3;3DP1 HLA: A*02,*32; B*27,*41; C*02,*07; DRB1*03,*16; DQB1*02,*05; Brother(M.M): KIR: 2DL2;2DL4(del);2DL5;2DS1; 2DS2;2DS4(del-22bp); 2DS5; 3DL1;3DL2;3DL3;3DP1 HLA:A*02,*24; B*08,*41; C*07,-; DRB1*03,-; DQB1*02,-; Brother(M.Z.): 2DS2;2DS4(del-22bp), 2DS5; 3DL1; 3DL2;3DL3;3DP1 Ludajić K. at al. Bone Marrow Transplantation 2009; 44: 97–103.

HLA haplotypes segregation analysis

KIR haplotypes segregation analysis

KIR 3DS1 segregate as 3DL1 3DL1*009 is formed by conversion between 3DL1*001 and 3DS1*01301

KIR genotypes frequencies Father (M.A.): CenB2/CenB2 and TelB1/TelB1 with frequency of 0,5-2,9% Mother (M.Z.): CenB2/CenB2 and TelA1/TelA1 with frequency of 0,5-6% Offsprings: CenB2/CenB2 and TelA1/TelB1 with frequency of 0,5-1% www.allelefrequencies.net

KIR 2DP1 and 2DL1 allele frequencies -Belgium 87% -Bulgaria, England, Germany 91% -Czech Republic 95% -Finland 100% -France 97% -Greece 89% -Iran 99% -Italy 95% 2DP1 -Belgium 99% -England 96-99% -Czech Republic 94% -France 98% -Portugal 89% -Iran 96% -Italy 96,9% www.allelefrequencies.net

Conclusion KIR and HLA analysis of presented family was interesting for a several reasons: 1) presence of rare KIR genotype with KIR 2DP1-2DL1 absence in both of parents and one mutualy shared haplotype (Cen-B2), 2) presence of probably hybrid KIR haplotype in offsprings and also rare KIR genotype with absence of KIR 2DP1-2DL1 genes 3) HLA identity between the father and the daughter, “best” B KIR gene content,1 KIR/HLA MM(3DL2)