Kozak Sequence Polymorphism of the Glycoprotein (GP) Ib Gene Is a Major Determinant of the Plasma Membrane Levels of the Platelet GP Ib-IX-V Complex

Despite the known importance of the sequences surrounding ATG start codons (Kozak sequences) for efficient translation of proteins, few reports have appeared that describe the natural variations in these sequences. Here, we report a human polymorphism in the Kozak sequence of the platelet adhesion receptor, glycoprotein (GP) Ib, a component of the GP Ib-IX-V complex, which mediates the initial adhesion of platelets to the blood vessel wall following injury. The polymorphism is based on the presence of either thymine (T) or cytosine (C) at position −5 from the initiator ATG in the GP Ib gene. The less common allele, −5C, represented 8% to 17% of the alleles in four ethnic populations surveyed. This allele more closely resembles the sequence considered optimal for efficient initiation of protein translation and is associated with increased expression of the receptor on the cell membrane, both in transfected cells and in the platelets of individuals carrying the allele. In vitro transcription/translation studies indicate that the increased expression results from more efficient translation of the −5C form of the GP Ib mRNA. Other mutations made to approximate more closely the consensus sequence described by Kozak did not increase expression of the receptor. This is the first known description of Kozak sequence polymorphism as a determinant of the surface levels of a cell adhesion receptor. This polymorphism may influence an individual’s susceptibility for the development of cardiovascular disease.