The contribution of familial resemblance to variation in circulatory levels of tissue inhibitors of metalloproteinases and transforming growth factor-β1

This study attempted to elucidate the genetic and environmental factors influencing interindividual variation of circulating TIMP-1, TIMP-2 and TGF-beta1 and to clarify the relationship between the latter biochemical indices and hand osteoarthritis in an ethnically homogeneous sample. Plasma levels of each of the above biochemical indices were measured in 401 healthy individuals (aged 18-75 years) belonging to 90 nuclear and more complex families. Variance component analysis showed that a major part of the interindividual differences in TGF-beta1, TIMP-1 and TIMP-2 levels was credibly attributable to genetic and familial factors. Adjusted for significant covariates, the putative genetic effects on the above three amounted to 0.40+/-0.10, 0.47+/-0.11 and 0.72+/-0.10, respectively. Common environmental factors, shared by members of the same household, also contributed significantly (P<0.01) to variation of each of the biochemical indices and explained between 27.6% (TIMP-2) and 38.7% (TGF-beta1) of their variation. A bivariate analysis revealed a strong and highly significant correlation between TIMP-1 and TGF-beta1 (r=0.58, P<0.001), which was due to common genetic and environmental sources (r(G)=0.62+/-0.09, r(E)=0.31+/-0.11, both P<0.001). The analysis also detected modest but significant genetic correlation between TIMP-1 and TIMP-2 (r(G)=-0.307+/-0.108, P<0.01). The present study evinces a strong genetic dependence for the plasma levels of both TIMPs and TGF-beta1 and provides a basis for the further analysis of genetic variation affecting and regulating the circulatory concentrations of TIMPs and TGF-beta1 in healthy humans.