Genetic determinants of 5-lipoxygenase pathway in a Spanish population and their relationship with cardiovascular risk

ObjectiveLeukotrienes (LT) play a role in inflammation, cardiovascular diseases, and cancer. Although some studies suggest that there are genes that determine variability of some LT-related phenotypes, the genetic influence on these phenotypes has not been evaluated.MethodsThe relative contributions of genetic and environmental influences to the 5-lipoxygenase pathway-related phenotypes (5-Lipoxygenase, five lipoxygenase activating protein (FLAP), LTA4-hydrolase and LTC4-synthase expression, and LTB4-plasma concentration and LTB4 production by stimulated whole blood) were assessed in a sample of 934 individuals in 35 extended families. Our design is based on extended families recruited through a probands with idiopathic thrombophilia. This strategy allows us the analysis of the effects of measured covariates (such as sex, age and smoking), genes, and environmental variables shared by members of a household.ResultsAll of these phenotypes showed significant genetic contributions, with heritabilities ranging from 0.33 to 0.51 for enzyme expression and from 0.25 to 0.50 for LTB4 production of the residual phenotypic variance. Significant phenotypic and genetic correlation among the LT-related traits was found. More importantly, FLAP and LTA4-hydrolase expression exhibit significant genetic correlations with arterial thrombosis, indicating that some of the genes that influence quantitative variation in these phenotypes also influence the risk of thrombosis.ConclusionThis is the first study that quantifies the genetic component of 5-Lipoxygenase pathway phenotypes. The high heritability of these traits and the significant genetic correlations between arterial thrombosis and some of these phenotypes suggest that the exploitation of correlated quantitative phenotypes will aid the search for susceptibility genes.

▸ We have studied genetic and environmental influences to the 5-LO pathway in humans. ▸ We studied extended families recruited through a probans with idiopathic thrombophilia. ▸ All 5-LO pathway-related phenotypes showed significant genetic contributions. ▸ Heritabilities of the phenotypes ranged from 0.33 to 0.51 for enzyme expression. ▸ FLAP and LTA4-hydrolase expression correlated with arterial thrombosis.