Non-HLA immunogenetic polymorphisms and the risk of complications after allogeneic hemopoietic stem-cell transplantation.
BACKGROUND
Existing data indicate that non-human leukocyte antigen (HLA) immunogenetic polymorphisms influence the risk of complications after allogeneic hemopoietic stem-cell transplantation. However, prior studies have been limited by small sample size and limited genotyping.


METHODS
We examined 22 polymorphisms in 11 immunoregulatory genes including cytokines, mediators of apoptosis, and host-defense molecules by polymerase chain reaction using sequence-specific primers in 160 related myeloablative transplants. Associations were confirmed in two independent cohorts.


RESULTS
An intronic polymorphism in the tumor necrosis factor gene (TNF 488A) was associated with the risk of acute graft-versus-host disease (GVHD) (odds ratio [OR] 16.9), grades II to IV acute GVHD (OR 3.3), chronic GVHD (OR 12.5), and early death posttransplant (OR 3.4). Recipient Fas -670G and donor interleukin (IL)-6 -174G were independent risk factors for acute GVHD. Recipient IL-10 ATA and Fas -670 genotype were independent risk factors for chronic GVHD. Recipient IL-1beta +3953T was associated with hepatic acute GVHD, and Fas -670G was associated with major infection.


CONCLUSIONS
These results highlight the potential importance of cytokine and apoptosis gene polymorphisms in stem-cell transplantation, and indicate that non-HLA genotyping may be useful to identify individuals at the highest risk of complications and new targets for therapeutic intervention.
Mullighan
Charles
C
Research and Development, Australian Red Cross Blood Service SA, Adelaide, Australia. cmull@senet.com.au
Heatley
Sue
S
Doherty
Kathleen
K
Szabo
Ferenc
F
Grigg
Andrew
A
Hughes
Timothy
T
Schwarer
Anthony
A
Szer
Jeff
J
Tait
Brian
B
To
Bik
B
Bardy
Peter
P
D000328:Adult; D001773:Blood Cells / Q000637:transplantation; D016026:Bone Marrow Transplantation; D002908:Chronic Disease; D015331:Cohort Studies; D016572:Cyclosporine / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D020022:Genetic Predisposition to Disease; D006086:Graft vs Host Disease / Q000235:genetics* / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007378:Interleukins / Q000235:genetics*; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D011110:Polymorphism, Genetic; D014184:Transplantation, Homologous / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D019014:fas Receptor / Q000235:genetics*
D007166:Immunosuppressive Agents; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D016572:Cyclosporine; D008727:Methotrexate