Table 2

Summary of MHC region polymorphisms associated with clinical outcome after allogeneic HCT

A. Candidate gene/polymorphismModelStudy populationEffectReference
HLA-G 14-bp insertion/deletion in 3′ UTR Homozygosity for del/del 53 HLA-matched URD Increased acute GVHD 59  
  Homozygosity for ins/ins 47 HLA-matched URD, siblings, cord blood Lower survival and DFS 61  
   157 HLA-identical siblings Increased severe acute GVHD 60  
HLA-E E*01:01 and E*01:03 alleles Patient and donor homozygosity for E*01:03 187 HLA-identical siblings (ref 54); 33 HLA-identical siblings, 12 HLA-matched URD; 11 haploidentical-mismatched related donors (ref 57) Lower grades 3-4 acute GVHD; lower TRM; improved survival 54,57  
  Patient E*01:03 homozygosity 67 HLA-matched siblings; 16 HLA matched URD Higher survival; higher DFS; lower TRM 55  
  Donor E*01:03 homozygosity 124 HLA-matched URD Lower grades 2-4 acute GVHD; lower chronic GVHD; higher relapse 56  
   116 HLA-matched URD No correlation with clinical outcome 58  
 E*01:01/01:03 Mismatch 116 HLA-matched URD No correlation with clinical outcome 58  
 Rs1264457 residue 128 arg (R) vs gly (G) Mismatch 922 HLA-matched and mismatched URD Lower survival 48  
MICA Residue 129 valine (V) versus methionine (M) Patients homozygous for 129V 211 HLA-matched siblings Higher chronic GVHD 50  
  Mismatch 236 HLA-matched and mismatched URD Higher grades 2-4 acute GVHD, notably gastrointestinal GVHD 51  
   38 HLA-matched URD No association 52  
  Binding affinity for M129V 38 HLA-matched URD No association 52  
 MICA*008 Patient genotype 38 HLA-matched URD Lower acute GVHD 52  
 MICA*004, 006, 009, 044, 049. Patient genotype 38 HLA-matched URD Higher gastrointestinal acute GVHD 52  
TNF Rs1799964 (-1031) Mismatch 922 HLA-matched and mismatched URD Higher grade 4 acute GVHD 48  
  Patient C genotype 180 HLA-matched URD Higher grades 3-4 acute GVHD 47  
  C genotype 182 HLA-matched and mismatched URD Higher TRM 45  
  Patient genotype, donor genotype 612 HLA-matched related donors; 686 HLA-matched URD No correlation 42  
 −1031/-863/-857 (rs1799724) U02/U03 alleles Patients and/or donors with U02 and/or U03 alleles 462 HLA-matched and mismatched URD Higher grades 3-4 acute GVHD and lower relapse 43  
 −308 Genotype 111 HLA-matched URD; 85 HLA matched siblings No correlation 44  
 Rs1800630 (-863) d4/d4 allele Patient genotype 180 HLA-matched URD Higher grades 3-4 acute GVHD 47  
   111 HLA-matched URD; 85 HLA matched siblings Higher grades 2-4 acute GVHD 44  
 D4/d5 microsatellite alleles Donor alleles 246 HLA-matched URD Higher mortality 49  
 Rs1800630* Patient genotype, donor genotype 612 HLA-matched related donors; 686 HLA-matched URD No correlation 42  
 RS1800629* Patient genotype, donor genotype 612 HLA-matched relateds; 686 HLA-matched URD No correlation 42  
HSPA1L +2763G/A Patients homozygous for AA genotype 63 HLA-matched siblings; 70 haploidentical related and HLA-matched URD Higher grades 2-4 acute GVHD; no correlation with donor HSPA1L or patient-donor match/mismatch 62  
 		Rs2075800 (see section C below)
 		Genotype; mismatch
 		922 HLA-matched and mismatched URD
 		No correlation
 		48 
 
B. GWAS chromosome 6 signals/closest locus
 		Model
 		Study population
 		Effect
 		Reference
 
Rs6937034
 		HLA-DP
 		Mismatch
 		1598 HLA-matched URD
 		Higher grades 2-4 acute GVHD
 		63 
 
C. “MHC-was”/Closest Locus
 		Model
 		Study Population
 		Effect
 		Reference
 
Rs209130‡ TRIM27 Mismatch 2628 HLA-mismatched URD Higher grades 3-4 acute GVHD 41  
rs2523957‡ HLA-A Mismatch (donor-versus-patient) 2628 HLA-mismatched URD Higher chronic GVHD 41  
rs887464† PSOR1C3/POU5F1 Mismatch (patient-versus-donor) 4205 HLA-matched URD Lower survival 40  
rs2244546‡ HCP5 Donor genotype GG 2628 HLA-mismatched URD Higher relapse 41  
rs915654‡ LTA Patient genotype AT 2628 HLA-mismatched URD Lower TRM 41  
Rs2242656‡ BAG6 Mismatch (donor-versus-patient) 2628 HLA-mismatched URD Higher grades 2-4 acute GVHD 41  
rs2075800‡ HSPA1L Patient genotype GG 2628 HLA-mismatched URD Higher grades 3-4 acute GVHD 41  
rs3830076‡ FKBPL Mismatch (donor-versus-patient) 2628 HLA-mismatched URD Lower chronic GVHD 41  
rs394657‡ NOTCH4 Donor genotype AA 2628 HLA-mismatched URD Lower grades 3-4 acute GVHD 41  
rs2071479‡ HLA-DOB Mismatch (donor-versus-patient) 2628 HLA-mismatched URD Higher chronic GVHD 41  
rs429916‡ HLA-DOA Patient genotype AA 2628 HLA-mismatched URD Lower survival 41  
Rs2281389† HLA-DPB1 3′UTR Mismatch 4205 HLA-matched URD Higher grades 2-4 acute GVHD 40  
rs986522‡ COL11A2 Donor genotype CG 2628 HLA-mismatched URD Lower relapse 41  
rs107822‡ RING1A Mismatch 2628 HLA-mismatched URD Higher chronic GVHD 41  
A. Candidate gene/polymorphismModelStudy populationEffectReference
HLA-G 14-bp insertion/deletion in 3′ UTR Homozygosity for del/del 53 HLA-matched URD Increased acute GVHD 59  
  Homozygosity for ins/ins 47 HLA-matched URD, siblings, cord blood Lower survival and DFS 61  
   157 HLA-identical siblings Increased severe acute GVHD 60  
HLA-E E*01:01 and E*01:03 alleles Patient and donor homozygosity for E*01:03 187 HLA-identical siblings (ref 54); 33 HLA-identical siblings, 12 HLA-matched URD; 11 haploidentical-mismatched related donors (ref 57) Lower grades 3-4 acute GVHD; lower TRM; improved survival 54,57  
  Patient E*01:03 homozygosity 67 HLA-matched siblings; 16 HLA matched URD Higher survival; higher DFS; lower TRM 55  
  Donor E*01:03 homozygosity 124 HLA-matched URD Lower grades 2-4 acute GVHD; lower chronic GVHD; higher relapse 56  
   116 HLA-matched URD No correlation with clinical outcome 58  
 E*01:01/01:03 Mismatch 116 HLA-matched URD No correlation with clinical outcome 58  
 Rs1264457 residue 128 arg (R) vs gly (G) Mismatch 922 HLA-matched and mismatched URD Lower survival 48  
MICA Residue 129 valine (V) versus methionine (M) Patients homozygous for 129V 211 HLA-matched siblings Higher chronic GVHD 50  
  Mismatch 236 HLA-matched and mismatched URD Higher grades 2-4 acute GVHD, notably gastrointestinal GVHD 51  
   38 HLA-matched URD No association 52  
  Binding affinity for M129V 38 HLA-matched URD No association 52  
 MICA*008 Patient genotype 38 HLA-matched URD Lower acute GVHD 52  
 MICA*004, 006, 009, 044, 049. Patient genotype 38 HLA-matched URD Higher gastrointestinal acute GVHD 52  
TNF Rs1799964 (-1031) Mismatch 922 HLA-matched and mismatched URD Higher grade 4 acute GVHD 48  
  Patient C genotype 180 HLA-matched URD Higher grades 3-4 acute GVHD 47  
  C genotype 182 HLA-matched and mismatched URD Higher TRM 45  
  Patient genotype, donor genotype 612 HLA-matched related donors; 686 HLA-matched URD No correlation 42  
 −1031/-863/-857 (rs1799724) U02/U03 alleles Patients and/or donors with U02 and/or U03 alleles 462 HLA-matched and mismatched URD Higher grades 3-4 acute GVHD and lower relapse 43  
 −308 Genotype 111 HLA-matched URD; 85 HLA matched siblings No correlation 44  
 Rs1800630 (-863) d4/d4 allele Patient genotype 180 HLA-matched URD Higher grades 3-4 acute GVHD 47  
   111 HLA-matched URD; 85 HLA matched siblings Higher grades 2-4 acute GVHD 44  
 D4/d5 microsatellite alleles Donor alleles 246 HLA-matched URD Higher mortality 49  
 Rs1800630* Patient genotype, donor genotype 612 HLA-matched related donors; 686 HLA-matched URD No correlation 42  
 RS1800629* Patient genotype, donor genotype 612 HLA-matched relateds; 686 HLA-matched URD No correlation 42  
HSPA1L +2763G/A Patients homozygous for AA genotype 63 HLA-matched siblings; 70 haploidentical related and HLA-matched URD Higher grades 2-4 acute GVHD; no correlation with donor HSPA1L or patient-donor match/mismatch 62  
 		Rs2075800 (see section C below)
 		Genotype; mismatch
 		922 HLA-matched and mismatched URD
 		No correlation
 		48 
 
B. GWAS chromosome 6 signals/closest locus
 		Model
 		Study population
 		Effect
 		Reference
 
Rs6937034
 		HLA-DP
 		Mismatch
 		1598 HLA-matched URD
 		Higher grades 2-4 acute GVHD
 		63 
 
C. “MHC-was”/Closest Locus
 		Model
 		Study Population
 		Effect
 		Reference
 
Rs209130‡ TRIM27 Mismatch 2628 HLA-mismatched URD Higher grades 3-4 acute GVHD 41  
rs2523957‡ HLA-A Mismatch (donor-versus-patient) 2628 HLA-mismatched URD Higher chronic GVHD 41  
rs887464† PSOR1C3/POU5F1 Mismatch (patient-versus-donor) 4205 HLA-matched URD Lower survival 40  
rs2244546‡ HCP5 Donor genotype GG 2628 HLA-mismatched URD Higher relapse 41  
rs915654‡ LTA Patient genotype AT 2628 HLA-mismatched URD Lower TRM 41  
Rs2242656‡ BAG6 Mismatch (donor-versus-patient) 2628 HLA-mismatched URD Higher grades 2-4 acute GVHD 41  
rs2075800‡ HSPA1L Patient genotype GG 2628 HLA-mismatched URD Higher grades 3-4 acute GVHD 41  
rs3830076‡ FKBPL Mismatch (donor-versus-patient) 2628 HLA-mismatched URD Lower chronic GVHD 41  
rs394657‡ NOTCH4 Donor genotype AA 2628 HLA-mismatched URD Lower grades 3-4 acute GVHD 41  
rs2071479‡ HLA-DOB Mismatch (donor-versus-patient) 2628 HLA-mismatched URD Higher chronic GVHD 41  
rs429916‡ HLA-DOA Patient genotype AA 2628 HLA-mismatched URD Lower survival 41  
Rs2281389† HLA-DPB1 3′UTR Mismatch 4205 HLA-matched URD Higher grades 2-4 acute GVHD 40  
rs986522‡ COL11A2 Donor genotype CG 2628 HLA-mismatched URD Lower relapse 41  
rs107822‡ RING1A Mismatch 2628 HLA-mismatched URD Higher chronic GVHD 41  

Part A: Candidate gene studies. In these studies, the specific MHC region gene or allele or SNP was tested individually. Genes are presented in chromosomal order. Part B: MHC region SNPs identified by GWAS of the entire genome. In this study, GWAS was performed using a commercial platform. Part C: SNPs identified by “MHC-was” SNPs survey. In these studies, SNPs genotyping was performed using commercial platforms. SNPs are presented in chromosomal order.

del, deletion; DFS, disease-free survival; ins, insertion.

*

SNP was imputed.42 

†

SNP was validated in a discovery-validation study design.40 

‡

SNP was identified in a discovery set; validation is pending.41 

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