A human lipoprotein polymorphism.

During the past decade, several groups of inherited human serum proteins constituting polymorphic systems have been discovered. These include the haptoglobins, transferrins, gamma globulin groups, and the group-specific substances (for review see Reference 1). In some of these systems the gene frequencies are such that a patient receiving repeated blood transfusions would have a high probability of receiving serum from an individual of a phenotype different from his own. For example, in a single transfusion, a European of haptoglobin type 1-1 (approximately 15 per cent of a European population) would have a chance of about 1 in 3 of receiving a serum of haptoglobin type 2-2 and a chance of about 1 in 2 of receiving type 2-1. Consideration of some of the other serum systems leads to the same general conclusion: a frequently transfused individual would almost certainly receive transfused plasma containing some proteins slightly different from his own. There is no evidence that any of the known differences among these proteins leads to antibody formation (2, 3). Nonetheless, under some circumstances and in some individuals either the known protein polymorphisms or other still undiscovered polymorphisms may induce isoimmunization. This has been considered possible for some time, and analogous findings are known in animals (4-6). In a study of human material, Allison and Blumberg (7) collected sera of patients who had required multiple transfusions for a variety of reasons and examined them for precipitating antibodies against normal human sera. With the Ouchterlony technique, a substance which acted as a precipitating antibody was found in the serum of a patient, C. de B., who had received approximately 50 transfusions because of a refractory anemia of unknown cause. The precipitin line was formed between the serum of C. de B. and some, but not all, normal sera (Figure 1). The antibody-like material in the serum of the transfused patient appeared to be 7S gamma globulin (7) and the "antigen" with which it reacted was a low-density beta-lipoprotein (8). Sera of 55 per cent of a U.S. population formed precipitin lines with this serum (see below), suggesting that the reacting "antigen" might be inherited. Preliminary population and family studies were consistent with the hypothesis that individuals homozygous for a recessive autosomal allele, termed Ag, were non-reactors, of phenotype Ag(a-). Those homozygous or heterozygous for its dominant allele AgO, those of phenotype Ag(a +), did react (7, 9). Additional studies are presented on the system determined by the C. de B. serum, the Ag (a) system, and further evidence for the genetic hypothesis is advanced. Other sera containing precipitins from transfused individuals have been found, and some of their properties will be described.