LightCyder peR for the Polymorphisms - 308 and - 238 in the TNF Alplla Gene IIiJI
tion, trauma and other noxious stimuli that can provoke a generalized systemic
inflammatory response [7]. It may thus become possible to target anti-TNF treatment specifically at those individuals genetically predisposed to produce high
amounts of this mediator after poly trauma. TNF is also a critical mediator in
rheumatoid arthritis and may therefore be a useful target for specific
immunotherapy. Indeed, beneficial responses in patients have been observed
after treatment with a chimeric monoclonal antibody to TNF (cA2) aiming to
reduce the amount of bioactive TNF [2]. Again here, analysis of TNF polymorphisms may become useful in selecting those individuals most likely to benefit
from this treatment. In recent developments, a critical role of the TNF system has
also been highlighted for diseases caused by prions. For example, TNF-a-deficient
mice have been shown resistant to peripheral infections with scrapie [16]. It is an
exciting possibility that genetic variations at the TNF loci may modulate the natural history of prion infections such as bovine spongiform encephalopathy (BSE
or mad cow disease) and the human new variant Creutzfeld-Jacob disease likely
caused by the same agent. In this and other fields of clinical investigation, methods for determining TNF locus variants such as those described here may find
widespread application in the near future.
References
1. Agarwal P, Oldenburg MC, Czarneski JE, Morse RM, Hameed MR, Cohen S, Fernandes H
(2000) Comparison study for identifying promoter allelic polymorphism in interleukin 10
and tumor necrosis factor alpha genes. Diagn Mol PathoI9:158-164
2. Baumgartner SW (2000) Tumor necrosis factor inactivation in the management of rheumatoid arthritis. South Med J 93:753-759
3. Braun J, Marz W, Winkelmann BR, Donner H, Henning Usadel K, Badenhoop K (1998)
Tumour necrosis factor ~ alleles an hyperinsulinaemia in coronary artery disease. Eur J Clin
Invest 28:538-542
4. Cabrera M, Shaw MA, Sharples C, Williams H, Castes M, Convit J, Blackwell JM (1995) Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis. J
Exp Med 182:1259-1264
5. Castro J, Telleria JJ, Linares P, Blanco-Quiros A (2000) Increased TNFA*2, but not TNFB*l,
allele frequency in Spanish atopic patients. J Investig Allergol Clin Immunol1O:149-154
6. Conway DJ, Holland MJ, Bailey RL, Campbell AE, Mahdi OS, Jennings R, Mbena E, Mabey DC
(1997) Scarring trachoma is associated with polymorphism in the tumor necrosis factor
alpha (TNF-alpha) gene promoter and with elevated TNF-alpha levels in tear fluid. Infect
Immun 65:1003-1006
7. Flach R, Majetschak M, Heukamp T, Jennissen V, Flohe S, Borgermann J, Obertacke U, Schade
FU (1999) Relation of ex vivo stimulated blood cytokine synthesis to post-traumatic sepsis.
Cytokine 11:173-178
8. Helmy N, Bestmann L, Garofalo F, Maly FE (2000) Tumor necrosis factor alpha polymorphism G-238A is associated with sepsis after trauma (abstract). Shock 13 [SuppIJ:486
9. Hohler T, Kruger A, Gerken G, Schneider PM, Meyer zum Buschenefelde KH, Rittner C
(1998) A tumor necrosis factor-alpha (TNF-alpha) promoter polymorphism is associated
with chronic hepatitis B infection. Clin Exp Immunol111:579-582
10. Hohler T, Kruger A, Gerken G, Schneider PM, Meyer zum Buschenfelde KH, Rittner C (1998)
Tumor necrosis factor alpha promoter polymorphism at position -238 is associated with
chronic active hepatitis C infection. J Med Virol 54: 173-177
tion, trauma and other noxious stimuli that can provoke a generalized systemic
inflammatory response [7]. It may thus become possible to target anti-TNF treatment specifically at those individuals genetically predisposed to produce high
amounts of this mediator after poly trauma. TNF is also a critical mediator in
rheumatoid arthritis and may therefore be a useful target for specific
immunotherapy. Indeed, beneficial responses in patients have been observed
after treatment with a chimeric monoclonal antibody to TNF (cA2) aiming to
reduce the amount of bioactive TNF [2]. Again here, analysis of TNF polymorphisms may become useful in selecting those individuals most likely to benefit
from this treatment. In recent developments, a critical role of the TNF system has
also been highlighted for diseases caused by prions. For example, TNF-a-deficient
mice have been shown resistant to peripheral infections with scrapie [16]. It is an
exciting possibility that genetic variations at the TNF loci may modulate the natural history of prion infections such as bovine spongiform encephalopathy (BSE
or mad cow disease) and the human new variant Creutzfeld-Jacob disease likely
caused by the same agent. In this and other fields of clinical investigation, methods for determining TNF locus variants such as those described here may find
widespread application in the near future.
References
1. Agarwal P, Oldenburg MC, Czarneski JE, Morse RM, Hameed MR, Cohen S, Fernandes H
(2000) Comparison study for identifying promoter allelic polymorphism in interleukin 10
and tumor necrosis factor alpha genes. Diagn Mol PathoI9:158-164
2. Baumgartner SW (2000) Tumor necrosis factor inactivation in the management of rheumatoid arthritis. South Med J 93:753-759
3. Braun J, Marz W, Winkelmann BR, Donner H, Henning Usadel K, Badenhoop K (1998)
Tumour necrosis factor ~ alleles an hyperinsulinaemia in coronary artery disease. Eur J Clin
Invest 28:538-542
4. Cabrera M, Shaw MA, Sharples C, Williams H, Castes M, Convit J, Blackwell JM (1995) Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis. J
Exp Med 182:1259-1264
5. Castro J, Telleria JJ, Linares P, Blanco-Quiros A (2000) Increased TNFA*2, but not TNFB*l,
allele frequency in Spanish atopic patients. J Investig Allergol Clin Immunol1O:149-154
6. Conway DJ, Holland MJ, Bailey RL, Campbell AE, Mahdi OS, Jennings R, Mbena E, Mabey DC
(1997) Scarring trachoma is associated with polymorphism in the tumor necrosis factor
alpha (TNF-alpha) gene promoter and with elevated TNF-alpha levels in tear fluid. Infect
Immun 65:1003-1006
7. Flach R, Majetschak M, Heukamp T, Jennissen V, Flohe S, Borgermann J, Obertacke U, Schade
FU (1999) Relation of ex vivo stimulated blood cytokine synthesis to post-traumatic sepsis.
Cytokine 11:173-178
8. Helmy N, Bestmann L, Garofalo F, Maly FE (2000) Tumor necrosis factor alpha polymorphism G-238A is associated with sepsis after trauma (abstract). Shock 13 [SuppIJ:486
9. Hohler T, Kruger A, Gerken G, Schneider PM, Meyer zum Buschenefelde KH, Rittner C
(1998) A tumor necrosis factor-alpha (TNF-alpha) promoter polymorphism is associated
with chronic hepatitis B infection. Clin Exp Immunol111:579-582
10. Hohler T, Kruger A, Gerken G, Schneider PM, Meyer zum Buschenfelde KH, Rittner C (1998)
Tumor necrosis factor alpha promoter polymorphism at position -238 is associated with
chronic active hepatitis C infection. J Med Virol 54: 173-177