Pharmacogenetics of steroid-responsive acute graft-versus-host disease.

TitlePharmacogenetics of steroid-responsive acute graft-versus-host disease.
Publication TypeJournal Article
Year of Publication2017
AuthorsArora, M, Weisdorf, DJ, Shanley, RM, Thyagarajan, B
JournalClin Transplant
Date Published2017 05
KeywordsAcute Disease, Adolescent, Adult, Aged, Child, Child, Preschool, Cohort Studies, Female, Follow-Up Studies, Genetic Markers, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation, Humans, Infant, Infant, Newborn, Male, Middle Aged, Pharmacogenetics, Prognosis, Steroids, Transplantation Conditioning, Transplantation, Homologous, Young Adult

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.

Alternate JournalClin Transplant
PubMed ID28266732
PubMed Central IDPMC5413396
Grant ListU10 HL069294 / HL / NHLBI NIH HHS / United States
UG1 HL069290 / HL / NHLBI NIH HHS / United States
P30 CA077598 / CA / NCI NIH HHS / United States
UL1 TR002494 / TR / NCATS NIH HHS / United States
U24 CA076518 / CA / NCI NIH HHS / United States
UG1 HL109137 / HL / NHLBI NIH HHS / United States