Genetic risk factors for sclerotic graft-versus-host disease.
Sclerotic graft-versus-host disease (GVHD) is a distinctive phenotype of chronic GVHD after allogeneic hematopoietic cell transplantation, characterized by fibrosis of skin or fascia. Sclerotic GVHD has clinical and histopathological similarities with systemic sclerosis, an autoimmune disease whose risk is influenced by genetic polymorphisms. We examined 13 candidate single-nucleotide polymorphisms (SNPs) that have a well-documented association with systemic sclerosis to determine whether these SNPs are also associated with the risk of sclerotic GVHD. The study cohort included 847 consecutive patients who were diagnosed with chronic GVHD. Genotyping was performed using microarrays, followed by imputation of unobserved SNPs. The donor rs10516487 (BANK1: B-cell scaffold protein with ankyrin repeats 1) TT genotype was associated with lower risk of sclerotic GVHD (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.21-0.87; P = .02). Donor and recipient rs2056626 (CD247: T-cell receptor ζ subunit) GG or GT genotypes were associated with higher risk of sclerotic GVHD (HR, 1.57; 95% CI, 1.13-2.18; P = .007 and HR, 1.66; 95% CI, 1.19-2.32; P = .003, respectively). Donor and recipient rs987870 (5'-flanking region of HLA-DPA1) CC genotypes were associated with higher risk of sclerotic GVHD (HR, 2.50; 95% CI, 1.22-5.11; P = .01 and HR, 2.13; 95% CI, 1.00-4.54; P = .05, respectively). In further analyses, the recipient DPA1*01:03∼DPB1*04:01 haplotype and certain amino acid substitutions in the recipient P1 peptide-binding pocket of the HLA-DP heterodimer were associated with risk of sclerotic GVHD. Genetic components associated with systemic sclerosis are also associated with sclerotic GVHD. HLA-DP-mediated antigen presentation, T-cell response, and B-cell activation have important roles in the pathogenic mechanisms of both diseases.
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA;
Yoshihiro
Y
Inamoto
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Medicine, and.
Paul J
0000-0001-9051-1215
PJ
Martin
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Medicine, and.
Mary E D
ME
Flowers
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Medicine, and.
Stephanie J
SJ
Lee
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA;
Paul A
PA
Carpenter
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Medicine, and.
Edus H
EH
Warren
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA;
Daniel E
DE
Geraghty
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA;
Ni
N
Lee
Department of Medicine, and Division of Vaccine and Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, WA;
Michael J
MJ
Boeckh
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA;
Barry E
BE
Storer
Department of Biostatics, University of Washington School of Medicine, Seattle, WA; and.
David M
DM
Levine
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
Wenhong
W
Fan
Department of Biostatics, University of Washington School of Medicine, Seattle, WA; and Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
Lue-Ping
LP
Zhao
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Medicine, and.
John A
JA
Hansen
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000235:genetics*; D000951:Antigens, Neoplasm / Q000235:genetics*; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006086:Graft vs Host Disease / Q000175:diagnosis* / Q000209:etiology / Q000473:pathology; D059867:HLA-DP alpha-Chains / Q000737:chemistry / Q000235:genetics*; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006650:Histocompatibility Testing; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011487:Protein Conformation; D012598:Sclerosis / Q000175:diagnosis* / Q000209:etiology / Q000473:pathology; D012871:Skin Diseases / Q000175:diagnosis* / Q000209:etiology / Q000473:pathology; D014184:Transplantation, Homologous; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000951:Antigens, Neoplasm; C447641:BANK1 protein, human; C078203:CD248 protein, human; D059867:HLA-DP alpha-Chains; C071172:HLA-DPA1 antigen; D008565:Membrane Proteins