ObjectiveControversial data have been reported on the association between the tumor necrosis factor (TNF)-&agr;–308 G&U279C;A promoter polymorphism or the TNF-&agr;NcoI polymorphism with TNF-&agr; 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-&agr; synthesis of activated granulocytes was studied.DesignAnalysis of TNF-&agr; concentrations of human whole blood after endotoxin stimulation.SettingMedical research laboratory.PatientsHealthy human volunteers.InterventionsNone.Measurements and Main ResultsHealthy human volunteers were genotyped for both TNF polymorphisms by means of polymerase chain reaction. TNF-&agr; plasma concentrations were determined with chemiluminescence after incubation of whole blood with endotoxin. A strong (p< .0001) linkage disequilibrium was found for the TNF-&bgr;NcoI and the TNF-&agr;–308 genetic polymorphisms. Almost all individuals homozygous for the TNF-B2 allele of the TNF-&bgr;NcoI polymorphism were also TNF-&agr;–308 G homozygotes. Carriers of the TNF-&agr;–308 genotype AG had a significantly higher TNF-&agr; production capacity than G homozygotes. The TNF-&bgr;NcoI genotype TNF-B1/TNF-B2 was associated with significantly higher TNF-&agr; concentrations than the genotype TNF-B2/TNF-B2. Individuals homozygous for the TNF-B2 and the TNF-&agr;–308 G alleles had a significantly reduced TNF-&agr; response compared with individuals heterozygous for both TNF polymorphisms.ConclusionsA 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-&agr; response.