Original Paper

LPA and PLG Sequence Variation and Kringle IV-2 Copy Number in Two Populations
Dana C. Crawford^a, Ze Peng^b, Jan-Fang Cheng^b, Dario Boffelli^b, Magdalena Ahearn^c, Dan Nguyen^c, Tristan Shaffer^c, Qian Yi^c, Robert J. Livingston^c, Mark J. Rieder^c, Deborah A. Nickerson<sup>c

a</sup>Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University, Nashville, Tenn.;
^bGenomics Division and Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, Calif.; and
^cDepartment of Genome Sciences, University of Washington, Seattle, Wash., USA

Address of Corresponding Author

Hum Hered 2008;66:199-209 (DOI: 10.1159/000143403)

  Key Words

• African-American
• Apo(a)
• Kringle
• Lp(a)
• Plasminogen
• Sequencing
• Linkage disequilibrium

  Abstract

Background/Aims: Lp(a) levels have long been recognized as a potential risk factor for coronary heart disease that is almost completely under genetic control. Much of the genetics impacting Lp(a) levels has been attributed to the highly polymorphic LPA kringle IV-2 copy number variant, and most of the variance in Lp(a) levels in populations of European-descent is inversely correlated with kringle IV copy number. However, less of the variance is explained in African-descent populations for the same structural variation. African-descent populations have, on average, higher levels of Lp(a), suggesting other genetic factors contribute to Lp(a) level variability across populations. Methods: To identify potential cis-acting factors, we re-sequenced the gene LPA for single nucleotide polymorphism (SNP) discovery in 23 European-Americans and 24 African-Americans. We also re- sequenced the neighboring gene plasminogen (PLG) and genotyped the kringle IV copy number variant in the same reference samples. Results: These data are the most comprehensive description of sequence variation in LPA and its relationship with the kringle IV copy number variant. With these data, we demonstrate that only a fraction of LPA sequence diversity has been previously documented. Also, we identify several high frequency SNPs present in the African-American sample but absent in the European-American sample. Finally, we show that SNPs within PLG are not in linkage disequilibrium with SNPs in LPA, and we show that kringle IV copy number variation is not in linkage disequilibrium with either LPA or PLG SNPs. Conclusions: Together, these data suggest that LPA SNPs could independently contribute to Lp(a) levels in the general population.

Copyright © 2008 S. Karger AG, Basel

  Author Contacts

Dana C. Crawford, PhD
Department of Molecular Physiology and Biophysics
Center for Human Genetics Research, Vanderbilt University
515B Light Hall, 2215 Garland Avenue, Nashville, TN 37232 (USA)
Tel. +1 615 343 7852, Fax +1 615 343 8619, E-Mail crawford@chgr.mc.vanderbilt.edu

  Article Information

Received: August 20, 2007
Accepted after revision: November 7, 2007
Published online: July 9, 2008
Number of Print Pages : 11
Number of Figures : 2, Number of Tables : 3, Number of References : 77