Linkage disequilibrium between tumor necrosis factor (TNF)-α-308 G/A promoter and TNF-β NcoI polymorphisms:: Association with TNF-α response of granulocytes to endotoxin stimulation

Objective. Controversial data have been reported on the association between the tumor necrosis factor (TNF)-alpha-308 GU279C;A promoter polymorphism or the TNF-alpha Ncol polymorphism with TNF-alpha plasma concentrations. The purpose of this study was to evaluate whether there is a linkage disequilibrium between the two polymorphisms. Moreover, the influence of these polymorphisms on the TNF-alpha synthesis of activated granulocytes was studied. Design. Analysis of TNF-alpha concentrations of human whole blood after endotoxin stimulation. Setting. Medical research laboratory. Patients. Healthy human volunteers. Interventions. None. Measurements and Main Results. Healthy human volunteers were genotyped for both TNF polymorphisms by means of polymerase chain reaction. TNF-alpha plasma concentrations were determined with chemiluminescence after incubation of whole blood with endotoxin. A strong (p <.0001) linkage disequilibrium was found for the TNF-beta Ncol and the TNF-alpha-308 genetic polymorphisms. Almost all individuals homozygous for the TNF-B2 allele of the TNF-beta Ncol polymorphism were also TNF-alpha-308 G homozygotes. Carriers of the TNF-alpha-308 genotype AG had a significantly higher TNF-alpha production capacity than G homozygotes. The TNF-beta Ncol genotype TNF-B1/TNF-B2 was associated with significantly higher TNF-alpha concentrations than the genotype TNF-B2/TNF-B2. Individuals homozygous for the TNF-B2 and the TNF-alpha-308 G alleles had a significantly reduced TNF-alpha response compared with individuals heterozygous for both TNF polymorphisms. Conclusions. A linkage disequilibrium between the two TNF polymorphisms was found. This study revealed a significant association between genotype and phenotype for both TNF polymorphisms. Heterozygosity for both TNF polymorphisms is associated with an increased TNF-alpha response.