ISOFORMS OF HUMAN C4B-BINDING PROTEIN .1. MOLECULAR-BASIS FOR THE C4BP ISOFORM PATTERN AND ITS VARIATIONS IN HUMAN PLASMA

Human C4b-binding protein (C4BP) is an important regulator of the comp lement system that also binds and inactivates the anticoagulant vitami n K-dependent protein S. These two activities are performed by two dis tinct polypeptides of 70 kDa and 45 kDa known as alpha- and beta-chain s, respectively. C4BP is present in plasma in various isoforms with di fferent cup composition. Here we report multiple discrete variations o f the relative levels of the C4BP isoforms among normal individuals an d provide evidence that they are determined by genetic factors that se gregate with the regulator of complement activation gene cluster. We a lso report the characterization of the C4BP molecules secreted by HepG 2 and Hep3B cells, as well as transfection experiments in COS cells, t o illustrate that the relative levels of expression of the C4BPA and C 4BPB genes play a major role in determining the proportion in which th e different C4BP isoforms are synthesized. Altogether, the data indica te that the human C4BP isoform pattern is genetically determined, but can be modified by factors with a differential effect on the expressio n of the C4BPA and C4BPB genes. These observations provide a new way t o explore the possible association between elevated levels of C4BP and an increased risk to thromboembolic disorders.