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

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Abstract
Objective Controversial data have been reported on the association between the tumor necrosis factor (TNF)-α–308 G➜A promoter polymorphism or the TNF-αNco I polymorphism with TNF-α 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-α synthesis of activated granulocytes was studied. Design Analysis of TNF-α 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-α plasma concentrations were determined with chemiluminescence after incubation of whole blood with endotoxin. A strong (p < .0001) linkage disequilibrium was found for the TNF-βNco I and the TNF-α–308 genetic polymorphisms. Almost all individuals homozygous for the TNF-B2 allele of the TNF-βNco I polymorphism were also TNF-α–308 G homozygotes. Carriers of the TNF-α–308 genotype AG had a significantly higher TNF-α production capacity than G homozygotes. The TNF-βNco I genotype TNF-B1/TNF-B2 was associated with significantly higher TNF-α concentrations than the genotype TNF-B2/TNF-B2. Individuals homozygous for the TNF-B2 and the TNF-α–308 G alleles had a significantly reduced TNF-α 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-α response.

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