Impact of Highly Conserved HLA Haplotype on Acute Graft-Versus-Host Disease in Unrelated Bone Marrow Transplantation

[INTRODUCTION] Although the effect of HLA locus and/or HLA antigen matching on clinical outcome of unrelated bone marrow transplantation (UR-BMT) has been well characterized, the effect of HLA haplotype (HP) itself is little known. The large scale genotyping of HLA-A, B, C, DRB1, DQB1, DPB1 alleles and SNPs among HLA region by whole genome association scans (WGAS) made it possible to ellucidate conserved common HPs and their impact to acute GVHD in HLA allele matched Japanese patient-donor pairs through Japan Marrow Donor Program.

[PATIENTS AND METHODS] 5210 patients who received T cell replete marrow were retrospectively typed for HLA-A, B, C, DRB1, DQB1 and DPB1 allele, and 1810 pairs performed WGAS using Affimetrics 500k array. HLA allele fullmatch was found in 712 pairs, of whom 451 pairs were genotyped 912 SNPs between HLA-A and HLA-DPB2 (from nucleotide 29989443 to 33205942, 3.2Mb). 45 common HLA-A, B, C, DRB1, DQB1, DPB1 HPs among Japanese (designated as HP-P1 to HP-P45) was determined according to the combination of HLA alleles. The probabilities of acute GVHD (grade 2–4) were estimated using the cumulative incidence function, where death without acute GVHD was regarded as a competing risk. Hazard risk (HR) of grade 2–4 acute GVHD was assesed by multivariable Cox regression analysis adjusting with 8 clincal factors.

[RESULTS] 1) 220 pairs determined both HPs, 354 one HP, 64 no HP and 74 HP with ambiguility of HP. There was no difference of acute GVHD between these 4 groups (26.7%, 33.2%, 28.6%, 35.8%, respectively). And that, donor and recipient mismatching rate of SNPs was not associated with acute GVHD; less than 5 mismatch SNPs (n=126) showed 32.2%, 6–50 (n=105) 32.4%, 51–100 (n=102) 27.5%, and more than 101 (n=118) 31.4%. 2) Most frequent HP (HP-P1: HLA- A*2402- Cw*1202- B*5201- DRB1*1502- DQB1*0601- DPB1*0901) was found in 331 pairs, and the second HP (HP-P2: HLA-A*3303- Cw*1403- B*4403- DRB1*1302- DQB1* 0604- DPB1*0401) in 111 pairs. 68 out of 72 homozygous HP-P1/P1 individuals had identical homozygous alleles for more than 98% of 912 consecutive SNPs. Of 10 HP-P2/P2 homozygous individuals, all individuals were identical homozygous alleles for 99% of 1310 consecutive SNPs extending from nucleotide 29001906 to 33987897 (4.9 Mb). Further more, 32 out of 34 heterozygous HP-P1/P2 individuals had more than 99% identical consecutive 912 alleles. 3) Considerable number of pairs with HP-P1 made it possible to compare another HPs for the risk of acute GVHD. Notably, 16.2% of acute GVHD in homozygous HP-P1/P1 pair (n=33) and 12.0% of acute GVHD in HP-P1/P2 pair (n=25) were significaitly lower than 39.1% in pair with HP-P1 and HP-P3-45 (n=246) (p=0.01), and HR was 0.41 (p=0.04) and 0.30 (p=0.04) respectively. 4) When analyzed an individual HP, patients with HP-P2 showed significant lower incidence of acute GVHD (22.3% n=111) than HP-P2 negative one (32.7% n=601) (p=0.031), and HR was 0.63 (p=0.032), and the other HPs did no significant difference.

[CONCLUSIONS]

1. Donor and recipient mismatching rate of SNPs in HLA region had no correlation with acute GVHD in HLA full matched UR-BMT in JMDP.

2. Common HP-P1 and HP-P2 were highly conserved through HLA-A to HLA-DPB2.

3. Patients with HP-P1/P1 and those with HP-P1/P2 showed lower incidence of acute GVHD, which is compatible with BMT from HLA identical sibling among Japanese.

4. Specific HP (HP-P2)itself reduced the incidence of acute GVHD.

These results contribute to favorable outcome of UR-BMT and to ellucidate the mechanism of acute GVHD.