Phenotypic sensitivity to activated protein C in healthy families: importance of genetic components and environmental factors

The relative importance of environmental factors and genetic components other than factor V Leiden on the sensitivity to activated protein C (APC) in healthy nuclear families was determined. We studied 149 European families (298 parents and 278 biological offspring aged more than 6 years). APC response was measured and expressed as normalized APC-sensitivity ratio (n-APC-SR). Subjects were genotyped for G1691A and G20210A polymorphisms of factor V and II genes; levels of factors II, V and VIII, antithrombin, cholesterol, high-density lipoprotein cholesterol and triglycerides were measured. After identifying variables influencing the n-APC-SR by a stepwise multiple regression model, variance component analysis was used. The heritability (proportion of the overall variability of a trait due to polygenic effects) of n-APC-SR was determined after adjustment for all clinical and laboratory variables, including factor V Leiden. Heritability coefficients (mean +/- standard deviation) were different for males (0.68 +/- 0.06) and females (0.34 +/- 0.12) younger than 25 years and in subjects older than 25 years: 0.37 +/- 0.09. This analysis provides strong evidence for a polygenic component influencing n-APC-SR in addition to factor V Leiden and suggests age- and gender-specific genetic effects.