Mapping MHC-resident transplantation determinants

Abstract

Graft-versus-host disease (GVHD) accounts for increased morbidity and mortality after HLA-identical unrelated hematopoietic cell transplantation (HCT). To test the hypothesis that the major histocompatibility complex (MHC) encodes functional variation other than the classical HLA genes, we measured risks associated with donor-recipient MHC microsatellite (Msat) marker mismatching in 819 HCT recipients and their HLA-A, -B, -C, -DRB1, and -DQB1 allele-matched unrelated donors. Suggestive trends of association with transplant outcome were observed for 5 Msats. Donor-recipient mismatching for the extended class I D6S105, class III D6S2787, and class II D6S2749 markers was each associated with an increased risk of death (hazard ratio, 1.32; 95% confidence interval, 1.02-1.71; P=.03; hazard ratio, 1.26; 95% confidence interval, 1.03-1.53; P=.02; hazard ratio, 1.37; 95% confidence interval, 1.08-1.72; P=.007, respectively) whereas mismatching for the class I D6S2811 marker was associated with a decreased risk of death (hazard ratio, 0.80; 95% confidence interval, 0.66-0.98; P=.03). Mismatching for the class I D6S265 marker was associated with a decreased risk of grades III-IV acute GVHD (odds ratio, 0.67; 95% confidence interval, 0.45-0.98; P=.04). These results suggest that Msats may be informative for mapping MHC-resident genetic variation of clinical importance in HCT.

Figure 1

Physical map of the MHC region and the location of Msat markers used in this study. Position of the Msats and HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, -DQA1, -DQB1, -DPA1, -DPB1, MICA, MICB and TNF are listed in map order from telomere to centromere on chromosome 6p21.3. Coordinates refer to National Center for Bioinformatics (NCBI) chromosome 6 build 36.2 (www.ncbi.nlm.nih.gov/mapview/maps.cgi?taxid=9606&chr=6, www.ncbi.nlm.nih.gov/sites/entrez?db=unists). The 3.1 Mb region between HLA-A to HLA-DPB1 is drawn to scale. The genetic distance is 3.6 Mb between D6S276 and D6S105 (single hatch), 2.1 Mb between D6S105 and HLA-A (double hatch) and 3.2 Mb between HLA-DPB1 and D6S291 (triple hatch). The kilobase (kb) pair distance between markers is provided in Table 1.

Figure 2

Rate of mismatching among HLA-A, -B, -C, -DRB1, -DQB1 matched donor-recipient study pairs for MHC region Msats. HLA loci are included for the purpose of orientation with respect to the Msats studied. Of the 819 study pairs, 704 (86 %) were each genotyped for all 12 Msats, 109 (13 %) for all Msats except D6S2810 and 6 pairs (3 %) for 10 or fewer Msats because of PCR failure. Of the 704 pairs, 11 (1.6%) were matched for all 12 Msat loci; the remaining 693 pairs were mismatched for 1 (1.2 %), 2 (2.1 %), 3 (2.1 %), 4 (6.2 %), or 5 or more (86.8%) Msats.