title: Pharmacogenetics of steroid-responsive acute graft-versus-host disease.
abstract: Glucocorticoids are central to effective therapy of acute graft-versus-host disease (GVHD). However, only about half of the patients respond to steroids in initial therapy. Based on postulated mechanisms for anti-inflammatory effectiveness, we explored genetic variations in glucocorticoid receptor, co-chaperone proteins, membrane transporters, inflammatory mediators, and variants in the T-cell receptor complex in hematopoietic cell transplant recipients with acute GVHD requiring treatment with steroids and their donors toward response at day 28 after initiation of therapy. A total of 300 recipient and donor samples were analyzed. Twenty-three SNPs in 17 genes affecting glucocorticoid pathways were included in the analysis. In multiple regression analysis, donor SNP rs3192177 in the ZAP70 gene (O.R. 2.8, 95% CI: 1.3-6.0, P=.008) and donor SNP rs34471628 in the DUSPI gene (O.R. 0.3, 95% CI: 0.1-1.0, P=.048) were significantly associated with complete or partial response. However, after adjustment for multiple testing, these SNPs did not remain statistically significant. Our results, on this small, exploratory, hypothesis generating analysis suggest that common genetic variation in glucocorticoid pathways may help identify subjects with differential response to glucocorticoids. This needs further assessment in larger datasets and if validated could help identify subjects for alternative treatments and design targeted treatments to overcome steroid resistance.
authors.affiliation: Hematology, Oncology and Transplant, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Mukta
authors.identifier: 0000-0001-9362-0556
authors.initials: M
authors.lastname: Arora
authors.affiliation: Hematology, Oncology and Transplant, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisdorf
authors.affiliation: Hematology, Oncology and Transplant, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Shanley
authors.affiliation: Lab Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Bharat
authors.initials: B
authors.lastname: Thyagarajan
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D005819:Genetic Markers; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011379:Prognosis; D013256:Steroids / Q000494:pharmacology*; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D055815:Young Adult
chemical_list: D005819:Genetic Markers; D013256:Steroids
keywords: SNPs; allogeneic; graft-versus-host disease; hematopoietic cell transplant; pharmacogenetics