Novel HLA-DP region susceptibility loci associated with severe acute GvHD.
Despite HLA allele matching, significant acute GvHD remains a major barrier to successful unrelated donor BMT. We conducted a genome-wide association study (GWAS) to identify recipient and donor genes associated with the risk of acute GvHD. A case-control design (grade III-IV versus no acute GvHD) and pooled GWA approach was used to study European-American recipients with hematological malignancies who received myeloablative conditioning non-T-cell-depleted first transplantation from HLA-A, -B, -C, -DRB1, -DQB1 allele level (10/10) matched unrelated donors. DNA samples were divided into three pools and tested in triplicate using the Affymetrix Genome-wide SNP Array 6.0. We identified three novel susceptibility loci in the HLA-DP region of recipient genomes that were associated with III-IV acute GvHD (rs9277378, P=1.58E-09; rs9277542, P=1.548E-06 and rs9277341, P=7.718E-05). Of these three single nucleotide polymorphisms (SNPs), rs9277378 and rs9277542 are located in non-coding regions of the HLA-DPB1 gene and the two are in strong linkage disequilibrium with two other published SNPs associated with acute GvHD, rs2281389 and rs9277535. Eighteen other recipient SNPs and 3 donor SNPs with a high level of significance (8E-07 or lower) were found. Our report contributes to emerging data showing clinical significance of the HLA-DP region genetic markers beyond structural matching of DPB1 alleles.
Department of Pediatric of Blood and Marrow Transplantation and Cellular Therapies, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.|Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Division of Hematology, Oncology and Blood and Marrow Transplantation, Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO, USA.
R K
RK
Goyal
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Department of Biostatistics, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA.
S J
SJ
Lee
Department of Biostatistics, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA.
T
T
Wang
Division of Immunogenetics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA, USA.
M
M
Trucco
Department of Immunobiology and Observational Research, Center for International Blood and Marrow Transplant Research, Minneapolis, MN, USA.
M
M
Haagenson
Department of Immunobiology and Observational Research, Center for International Blood and Marrow Transplant Research, Minneapolis, MN, USA.
S R
SR
Spellman
Department of Pediatric BMT, University of Minnesota, Minneapolis, MN, USA.
M
M
Verneris
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
R E
RE
Ferrell
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D064591:Allografts; D016026:Bone Marrow Transplantation; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006086:Graft vs Host Disease / Q000235:genetics*; D059868:HLA-DP beta-Chains / Q000235:genetics*; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000628:therapy; D006801:Humans; D007223:Infant; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D061349:Unrelated Donors
D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen