Genetic and environmental influences on IL-6 and TNF-alpha plasma levels in apparently healthy general population

Dysregulation of cytokines synthesis is thought to play a role in the development of a number of age-related conditions, such as rheumatoid arthritis, osteoporosis, atherosclerosis, and others, but observational studies have led to contradictory results. We investigated potential familial influences on the plasma levels of IL-6 and TNF-alpha in 91 nuclear and more complex pedigrees of Caucasian ethnic origin (N=401 individuals). The maximum likelihood based variance decomposition analysis showed significant positive correlation between circulating IL-6 and age in both genders. The magnitude of these correlations in our sample ranged from 0.22 in females to 0.28 in males (P<0.001). Significant association between TNF-alpha and IL-6 (r=0.28, r=0.43; P<0.001; respectively for men and women) was also observed. Likelihood ratio test clearly revealed that additive genetic effect for TNF-alpha was highly significant (P<0.001), and accounted over 80% of its variation, adjusted for IL-6 levels and age. In contrast, heritability estimate for IL-6 adjusted for age and TNF-alpha, revealed small contribution of genetic factors (24.1 +/- 10.2%). The bivariate variance component analysis demonstrated that significant relationship between IL-6 and TNF-alpha was due to shared environment only (r(E)=0.760 +/- 0.140). As evinced from our complex segregation analysis the nature of the genetic determinant of each of these two cytokines is quite complex and it is probably oligogenic.