Lp(a) is an atherogenic lipoprotein that contains a unique glycoprotein, apolipoprotein [apo(a)]. Apo (a) isoforms exhibit enormous size variation among individuals. Elucidation of the molecular basis of this variability was hampered by technical problems in dealing with a gene containing multiple repeated sequences that are shared with plasminogen and several pseudogenes. The investigator overcame many of these problems by using pulsed-field gel electrophoresis to identify a fragment of genomic DNA that contains most of the exons encoding kringle 4, the major repeated sequence in apo(a). The size of this genomic fragment correlates with the size of the apo(a) protein in different individuals, indicating that different apo(a) alleles posses different numbers of kringle 4-encoding repeats. This discovery provided a molecular handle with which to analyze the apo(a) gene directly, and to examine its role in determining the plasma level of Lp(a) in humans. The investigator has shown in Caucasians that the sequence variation in the apo(a) gene is the most important determinant of plasma Lp(a) levels. The specific questions that the investigator will now address are : 1) Why do plasma levels of Lp(a) vary between Caucasians and African-Americans? 2) How much of this variation is due to differences at the apo(a) locus? 3) What are the structural determinants at the apo(a) locus that affect the plasma level and at the atherogenicity of Lp(a)? 4) And finally, do genes that influence LDL metabolism modulate the levels of plasma Lp(a)? To answer these questions, the investigator will perform : 1) Family studies to determine if the plasma level of Lp(a) segregates with the apo(a) gene in African-Americans; 2) Pedigree analysis to determine the effect of mutations in the LDL receptor and apo(B) genes on the plasma level of Lp(a); 3) Molecular characterization of selected apo(a) alleles which are associated with either high, or low levels of plasma Lp(a); 4) Molecular characterization of apo(a) alleles associated with coronary artery disease; 5) and finally, tissue culture and animal studies designed to express the apo(a) gene in its authentic genomic context. By learning more about the apo(a) gene structure and its relation to the plasma level of Lp(a) the investigator will gain insights into the mechanisms underlying the role of Lp(a) in atherogenesis.
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