Genetic determinants of variation in the plasma levels of the C4b-binding protein (C4BP) in Spanish families

The C4b-binding protein (C4BP) is a plasma glycoprotein implicated in the homeostasis of the complement and coagulation systems. It is composed of two polypeptides (α and β), which form three plasma oligomers with different subunit compositions (α₇β₁, α₇β₀, and α₆β₁). The β chain-containing C4BP isoforms (C4BPβ⁺ isoforms) bind and inactivate protein S (PS), downregulating the activated protein C (APC)-dependent anticoagulatory pathway. Because PS deficiency is associated with recurrent thrombosis, it has been suggested that increased levels of C4BPβ⁺ isoforms might diminish the free PS plasma level, affecting the risk of developing thromboembolism. Previous work has tested this hypothesis, but no definitive conclusions were reached, mostly because nothing is known about the factors influencing the high variability in C4BP plasma levels in humans. As a part of the GAIT project, using variance component analysis, this work provides the first estimation of the relative contributions of genetic and environmental influences on the plasma levels of total C4BP and C4BPβ⁺ isoforms. Plasma levels of total C4BP and C4BPβ⁺ isoforms showed strong evidence of genetic regulation (heritability 37.7% and 42.5%, respectively). They were also affected by age, smoking, and exogenous sex hormones. Our results constitute the first step in localizing and evaluating potential quantitative trait loci that affect the plasma levels of C4BP and C4BPβ⁺. Furthermore, analysis of phenotypic and genetic correlations between C4BPβ⁺ plasma levels and the components of the APC anticoagulatory pathway (total PS, free PS, functional PS, and functional PC) suggests a genetic coregulation of the proteins. These observations might have important implications in the individual susceptibility to thrombotic disease.