(Circulation. 1999;100:e84.)
© 1999 American Heart Association, Inc.
Circulation Electronic Pages |
Tumor Necrosis Factor-
and Interleukin-10 Genotypes in Congestive Heart Failure
Wythenshawe Hospital Manchester, UK
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Introduction |
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 Top Introduction References |
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To the Editor:
The allelic case-control study by Kubota et al1 suggests
that polymorphisms at positions -308 and +252 of the tumor
necrosis factor-
(TNF-) gene do not influence either risk of
heart failure or plasma levels of TNF- for patients with heart
failure. The investigators recognize the potential biases of patient
selection inherent in the study and suggest that patients homozygous
for TNFA2 or TNFB2 could have had a more "malignant" clinical
course such that mortality was high before presentation at
a participating center. However, the isolated assessment of TNF-
genotypes and plasma levels may be misleading without
consideration of other interacting cytokines.
Although TNFA2 and TNFB2 have been correlated with increased TNF-
release by endotoxin-stimulated leukocytes, in vivo control of TNF-
synthesis is complex and downregulated by anti-inflammatory
cytokines including interleukin (IL)-4 and IL-10. An
autoregulatory loop appears to exist whereby TNF- induces IL-10
production, which ultimately reduces TNF-
synthesis.2 Three functional polymorphisms have been
described for the IL-10 promoter, with single base pair substitutions
at positions -1082, -819, and -592.3 In particular,
substitution of guanine for adenine at position -1082 has been
correlated with low IL-10 production after T-cell
stimulation.3 The potential clinical importance of this
finding was highlighted by a recent study4 demonstrating a
strong association between the combined low IL-10/high TNF- (TNFA2)
genotype and early graft rejection in a population of heart
transplant recipients. Other recent studies5 have
demonstrated the complementary importance of IL-10 and TNF- in
patients with bacterial sepsis and have indicated an increased
mortality in patients with a high plasma IL-10 to TNF- ratio.
Selection pressures may therefore exist to ensure persistence of the
high TNF-/low IL-10 genotype because of potential resistance
to bacterial infection. Further studies are warranted to assess whether
this combined genotype predisposes toward the development of
heart failure in an unselected population.
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References |
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TopIntroductionReferences |
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1. Kubota T, McNamara DM, Wang JJ, Trost M, McTiernan CF, Mann DL, Feldman AM, for the VEST Investigators for TNF Genotype Analysis. Effects of tumor necrosis factor gene polymorphisms on patients with congestive heart failure. Circulation. 1998;97:2499–2501.
2.
van der Poll T, Jansen J, Levi M, ten Cate H, ten Cate
JW, van Deventer SJ. Regulation of interleukin 10 release by tumor
necrosis factor in humans and chimpanzees. J Exp Med. 1994;180:1985–1988.
3. Turner D, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV. An investigation of polymorphism in the interleukin-10 promoter. Eur J Immunogen. 1997;24:1–8.[Medline] [Order article via Infotrieve]
4. Turner D, Grant SCD, Yonan N, Sheldon S, Dyer PA, Sinnott PJ, Hutchinson IV. Cytokine gene polymorphism and heart transplant rejection. Transplantation. 1997;64:776–779.[Medline] [Order article via Infotrieve]
5. van Dissel JT, van Langevelde P, Westendorp RGJ, Kwappenberg K, Frolich M. Anti-inflammatory cytokine profile and mortality in febrile patients. Lancet. 1998;351:950–953.[Medline] [Order article via Infotrieve]
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