title: Single nucleotide polymorphisms and outcome risk in unrelated mismatched hematopoietic stem cell transplantation: an exploration study.
abstract: Genetic risk factors contribute to adverse outcome of hematopoietic stem cell transplantation (HSCT). Mismatching of the HLA complex most strongly determines outcomes, whereas non-HLA genetic polymorphisms are also having an impact. Although the majority of HSCTs are mismatched, only few studies have investigated the effects of non-HLA polymorphisms in the unrelated HSCT and HLA-mismatched setting. To understand these effects, we genotyped 41 previously studied single nucleotide polymorphisms (SNPs) in 2 independent, large cohorts of HSCT donor-recipient pairs (n = 460 and 462 pairs) from a homogeneous genetic background. The study population was chosen to pragmatically represent a large clinically homogeneous group (acute leukemia), allowing all degrees of HLA matching. The TNF-1031 donor-recipient genotype mismatch association with acute GVHD grade 4 was the only consistent association identified. Analysis of a subgroup of higher HLA matching showed consistent associations of the recipient IL2-330 GT genotype with risk of chronic GVHD, and the donor CTLA4-CT60 GG genotype with protection from acute GVHD. These associations are strong candidates for prediction of risk in a clinical setting. This study shows that non-HLA gene polymorphisms are of relevance for predicting HSCT outcome, even for HLA mismatched transplants.
authors.affiliation: Division of Molecular Life Sciences, Tokai University School of Medicine, Kanagawa, Japan. christian.harkensee@ncl.ac.uk
authors.forename: Christian
authors.initials: C
authors.lastname: Harkensee
authors.forename: Akira
authors.initials: A
authors.lastname: Oka
authors.forename: Makoto
authors.initials: M
authors.lastname: Onizuka
authors.forename: Peter G
authors.initials: PG
authors.lastname: Middleton
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Inoko
authors.forename: Kouyuki
authors.initials: K
authors.lastname: Hirayasu
authors.forename: Koichi
authors.initials: K
authors.lastname: Kashiwase
authors.forename: Toshio
authors.initials: T
authors.lastname: Yabe
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nakaoka
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Gennery
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ando
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Morishima
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006680:HLA Antigens / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000628:therapy*; D012189:Retrospective Studies; D016896:Treatment Outcome; D061349:Unrelated Donors; D055815:Young Adult
chemical_list: D006680:HLA Antigens