Genetic determinants of circulating levels of tumor necrosis factor receptor II and their association with TNF-RII gene polymorphisms

Background: Tumor necrosis factor alpha (TNFα) is a cytokine involved in inflammatory, immune, and metabolic events. TNFα signals are mediated through activation of two receptors, one of which is tumor necrosis factor receptor TNF-RII. Objective: To examine the effects of genetic and environmental factors on TNF-RII plasma concentration and its association with polymorphisms in the TNF-RII gene locus. Methods: The levels of sTNF-RII were determined in 897 individuals. The association between sTNF-RII and polymorphisms in its structural gene locus was examined by pedigree-based association analyses (PDT) and transmission disequilibrium tests (TDTs). Results: 49.57% of the adjusted sTNF-RII variability was attributable to genetic factors. sTNF-RII plasma levels were nominally associated with the genomic region spanning TNF-RII promoter and the first intron, represented by rs976881 (p=0.029). Although after correction for multiple testing this PDT signal formally did not reach statistical significance, it was reflected also in series of TDTs and further confirmed by association observed for haplotype of rs976881 with rs590368 (nominal p=0.006) and by ANOVA. Conclusions: sTNF-RII plasma concentration is determined by both genetic and environmental factors. Our results suggest association between sTNF-RII levels and polymorphisms in vicinity to TNF-RII promoter region. This finding requires further thorough validation in other populations.