LP(a) is an atherogenic lipoprotein that is distinguished by its content of apolipoprotein [apo(a)]. Although the apo(a) cDNA was cloned in 1987, the apo(a) gene has not been characterized, due to technical problems in dealing with a gene containing multiple repeated sequences that are shared with plasminogen and several pseudogenes. We have overcome many of these problems by using pulsed-field gel electrophoresis to define a fragment of genomic DNA that contains all of the exons encoding kringle 4, the major repeated sequence in apo(a). The size of this genomic fragment, which ranges from 50 kb to 190 kb, correlates with the variable size of the apo(a) protein in different individuals, owing to the fact that different alleles possess different numbers of kringle 4- encoding repeats. This discovery provides a molecular handle with which to analyze the apo(a) gene directly, and to examine its role in determining the level of Lp(a) in humans. The specific questions that will be addressed are: 1) Why do plasma levels of Lp(a) vary between individuals and different ethnic groups? 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 of Lp(a)? 4) And finally, do genes that influence LDL metabolism modulate the level of plasma Lp(a)? To answer these questions we will perform: 1) Population studies to determine the relationship between the size of the apo(a) gene and the plasma level of Lp(a), and to determine the genetic basis of the differences in Lp(a) levels that occur in different populations. 2) Family studies to determine if the plasma level of Lp(a) segregates with the apo(a) gene. 3) Molecular characterization of selected apo(a) alleles which are associated with either high, or low levels of plasma Lp(a). 4) And finally, pedigree analysis to determine the effect of mutations in the LDL receptor and apo(B) genes on the plasma level of Lp(a). By learning more about the apo(a) gene structure and its regulation to the plasma level of Lp(a), we hope to gain insights into the mechanisms underlying high Lp(a) levels in many individuals, and hopefully, these studies will help in the eventual unraveling of the mechanism by which Lp(a) accelerates atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL047619-03
Application #
2223806
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1992-02-01
Project End
1995-01-31
Budget Start
1994-02-01
Budget End
1995-01-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Genetics
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Guerra, Rudy; Yu, Zhaoxia; Marcovina, Santica et al. (2005) Lipoprotein(a) and apolipoprotein(a) isoforms: no association with coronary artery calcification in the Dallas Heart Study. Circulation 111:1471-9
Arca, Marcello; Zuliani, Giovanni; Wilund, Kenneth et al. (2002) Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH: a clinical and molecular genetic analysis. Lancet 359:841-7
Wang, J; Boedeker, J; Hobbs, H H et al. (2001) Determinants of human apolipoprotein [a] secretion from mouse hepatocyte cultures. J Lipid Res 42:60-9
Acquati, F; Hammer, R; Ercoli, B et al. (1999) Transgenic mice expressing a human apolipoprotein[a] allele. J Lipid Res 40:994-1006
Tao, R; Acquati, F; Marcovina, S M et al. (1999) Human growth hormone increases apo(a) expression in transgenic mice. Arterioscler Thromb Vasc Biol 19:2439-47
Hobbs, H H; White, A L (1999) Lipoprotein(a): intrigues and insights. Curr Opin Lipidol 10:225-36
Mooser, V; Scheer, D; Marcovina, S M et al. (1997) The Apo(a) gene is the major determinant of variation in plasma Lp(a) levels in African Americans. Am J Hum Genet 61:402-17
Mooser, V; Marcovina, S M; Wang, J et al. (1997) High plasma levels of apo(a) fragments in Caucasians and African-Americans with end-stage renal disease: implications for plasma Lp(a) assay. Clin Genet 52:387-92
Marcovina, S M; Hobbs, H H; Albers, J J (1996) Relation between number of apolipoprotein(a) kringle 4 repeats and mobility of isoforms in agarose gel: basis for a standardized isoform nomenclature. Clin Chem 42:436-9
Mooser, V; Marcovina, S M; White, A L et al. (1996) Kringle-containing fragments of apolipoprotein(a) circulate in human plasma and are excreted into the urine. J Clin Invest 98:2414-24

Showing the most recent 10 out of 22 publications