Donor-recipient mismatch for common gene deletion polymorphisms in graft-versus-host disease.
Transplantation and pregnancy, in which two diploid genomes reside in one body, can each lead to diseases in which immune cells from one individual target antigens encoded in the other's genome. One such disease, graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT, or bone marrow transplant), is common even after transplants between HLA-identical siblings, indicating that cryptic histocompatibility loci exist outside the HLA locus. The immune system of an individual whose genome is homozygous for a gene deletion could recognize epitopes encoded by that gene as alloantigens. Analyzing common gene deletions in three HSCT cohorts (1,345 HLA-identical sibling donor-recipient pairs), we found that risk of acute GVHD was greater (odds ratio (OR) = 2.5; 95% confidence interval (CI) 1.4-4.6) when donor and recipient were mismatched for homozygous deletion of UGT2B17, a gene expressed in GVHD-affected tissues and giving rise to multiple histocompatibility antigens. Human genome structural variation merits investigation as a potential mechanism in diseases of alloimmunity.
McCarroll
Steven A
SA
Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. mccarroll@genetics.med.harvard.edu
Bradner
James E
JE
Turpeinen
Hannu
H
Volin
Liisa
L
Martin
Paul J
PJ
Chilewski
Shannon D
SD
Antin
Joseph H
JH
Lee
Stephanie J
SJ
Ruutu
Tapani
T
Storer
Barry
B
Warren
Edus H
EH
Zhang
Bo
B
Zhao
Lue Ping
LP
Ginsburg
David
D
Soiffer
Robert J
RJ
Partanen
Jukka
J
Hansen
John A
JA
Ritz
Jerome
J
Palotie
Aarno
A
Altshuler
David
D
D016026:Bone Marrow Transplantation; D015331:Cohort Studies; D005260:Female; D017353:Gene Deletion; D015894:Genome, Human; D014453:Glucuronosyltransferase / Q000235:genetics; D006086:Graft vs Host Disease / Q000235:genetics* / Q000276:immunology; D006680:HLA Antigens / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D015778:Minor Histocompatibility Antigens; D011110:Polymorphism, Genetic
D006680:HLA Antigens; D015778:Minor Histocompatibility Antigens; D014453:Glucuronosyltransferase; C500513:UGT2B17 protein, human