Non-HLA immunogenetic polymorphisms and the risk of complications after allogeneic hemopoietic stem-cell transplantation

Charles Mullighan, Sue Heatley, Kathleen Doherty, Ferenc Szabo, Andrew Grigg, Timothy Hughes, Anthony Schwarer, Jeff Szer, Brian Tait, Bik To, Peter Bardy

Research output: Contribution to journalArticle

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Abstract

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-1β +3953T was associated with hepatic acute GVHD, and Fas -670G was associated with major infection. Conclusion. 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.

LanguageEnglish
Pages587-596
Number of pages10
JournalTransplantation
Volume77
Issue number4
DOIs
Publication statusPublished - 27 Feb 2004
Externally publishedYes

ASJC Scopus subject areas

  • Transplantation

Cite this

Mullighan, Charles ; Heatley, Sue ; Doherty, Kathleen ; Szabo, Ferenc ; Grigg, Andrew ; Hughes, Timothy ; Schwarer, Anthony ; Szer, Jeff ; Tait, Brian ; To, Bik ; Bardy, Peter. / Non-HLA immunogenetic polymorphisms and the risk of complications after allogeneic hemopoietic stem-cell transplantation. In: Transplantation. 2004 ; Vol. 77, No. 4. pp. 587-596.
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Non-HLA immunogenetic polymorphisms and the risk of complications after allogeneic hemopoietic stem-cell transplantation. / Mullighan, Charles; Heatley, Sue; Doherty, Kathleen; Szabo, Ferenc; Grigg, Andrew; Hughes, Timothy; Schwarer, Anthony; Szer, Jeff; Tait, Brian; To, Bik; Bardy, Peter.

In: Transplantation, Vol. 77, No. 4, 27.02.2004, p. 587-596.

Research output: Contribution to journalArticle

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T1 - Non-HLA immunogenetic polymorphisms and the risk of complications after allogeneic hemopoietic stem-cell transplantation

AU - Mullighan, Charles

AU - Heatley, Sue

AU - Doherty, Kathleen

AU - Szabo, Ferenc

AU - Grigg, Andrew

AU - Hughes, Timothy

AU - Schwarer, Anthony

AU - Szer, Jeff

AU - Tait, Brian

AU - To, Bik

AU - Bardy, Peter

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N2 - 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-1β +3953T was associated with hepatic acute GVHD, and Fas -670G was associated with major infection. Conclusion. 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.

AB - 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-1β +3953T was associated with hepatic acute GVHD, and Fas -670G was associated with major infection. Conclusion. 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.

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