Single-nucleotide Polymorphisms in LPA Explain Most of the Ancestry-specific Variation in Lp(a) Levels in African Americans

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2011 Feb 2

PMID 21283670

Citations 33

Authors

Rahul C Deo

James G Wilson

Chao Xing

Kim Lawson

W H Linda Kao

David Reich

Arti Tandon

Ermeg Akylbekova

Nick Patterson

Thomas H Mosley Jr

Eric Boerwinkle

Herman A Taylor Jr

Affiliations

Soon will be listed here.

Abstract

Lipoprotein(a) (Lp(a)) is an important causal cardiovascular risk factor, with serum Lp(a) levels predicting atherosclerotic heart disease and genetic determinants of Lp(a) levels showing association with myocardial infarction. Lp(a) levels vary widely between populations, with African-derived populations having nearly 2-fold higher Lp(a) levels than European Americans. We investigated the genetic basis of this difference in 4464 African Americans from the Jackson Heart Study (JHS) using a panel of up to 1447 ancestry informative markers, allowing us to accurately estimate the African ancestry proportion of each individual at each position in the genome. In an unbiased genome-wide admixture scan for frequency-differentiated genetic determinants of Lp(a) level, we found a convincing peak (LOD = 13.6) at 6q25.3, which spans the LPA locus. Dense fine-mapping of the LPA locus identified a number of strongly associated, common biallelic SNPs, a subset of which can account for up to 7% of the variation in Lp(a) level, as well as >70% of the African-European population differences in Lp(a) level. We replicated the association of the most strongly associated SNP, rs9457951 (p = 6 × 10(-22), 27% change in Lp(a) per allele, ∼5% of Lp(a) variance explained in JHS), in 1,726 African Americans from the Dallas Heart Study and found an even stronger association after adjustment for the kringle(IV) repeat copy number. Despite the strong association with Lp(a) levels, we find no association of any LPA SNP with incident coronary heart disease in 3,225 African Americans from the Atherosclerosis Risk in Communities Study.

Citing Articles

Lipoprotein (a) as a Cardiovascular Risk Factor in Controversial Clinical Scenarios: A Narrative Review.

Abdalla H, Mahmoud A, Khedr A, Farina J, Scalia I, Abbas M Int J Mol Sci. 2024; 25(20).

PMID: 39456811 PMC: 11507037. DOI: 10.3390/ijms252011029.

Association between lipoprotein (a) and risk of atherosclerotic cardiovascular disease events among maintenance hemodialysis patients in Beijing, China: a single-center, retrospective study.

Liang Q, Zhang G, Jiang L BMC Nephrol. 2024; 25(1):250.

PMID: 39090533 PMC: 11295529. DOI: 10.1186/s12882-024-03690-z.

Lipoprotein(a): Just an Innocent Bystander in Arterial Hypertension?.

Brosolo G, Da Porto A, Marcante S, Picci A, Capilupi F, Capilupi P Int J Mol Sci. 2023; 24(17).

PMID: 37686169 PMC: 10487946. DOI: 10.3390/ijms241713363.

Evidence and Uncertainties on Lipoprotein(a) as a Marker of Cardiovascular Health Risk in Children and Adolescents.

Genovesi S, Giussani M, Lieti G, Orlando A, Patti I, Parati G Biomedicines. 2023; 11(6).

PMID: 37371756 PMC: 10295837. DOI: 10.3390/biomedicines11061661.

Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement.

Kronenberg F, Mora S, Stroes E, Ference B, Arsenault B, Berglund L Eur Heart J. 2022; 43(39):3925-3946.

PMID: 36036785 PMC: 9639807. DOI: 10.1093/eurheartj/ehac361.

References

White A, Hixson J, Rainwater D, Lanford R . Molecular basis for "null" lipoprotein(a) phenotypes and the influence of apolipoprotein(a) size on plasma lipoprotein(a) level in the baboon. J Biol Chem. 1994; 269(12):9060-6. View

Reich D, Patterson N, Ramesh V, De Jager P, McDonald G, Tandon A . Admixture mapping of an allele affecting interleukin 6 soluble receptor and interleukin 6 levels. Am J Hum Genet. 2007; 80(4):716-26. PMC: 1852718. DOI: 10.1086/513206. View

Chretien J, Coresh J, Berthier-Schaad Y, Kao W, Fink N, Klag M . Three single-nucleotide polymorphisms in LPA account for most of the increase in lipoprotein(a) level elevation in African Americans compared with European Americans. J Med Genet. 2006; 43(12):917-23. PMC: 2563202. DOI: 10.1136/jmg.2006.042119. View

Granek J, Clarke N . Explicit equilibrium modeling of transcription-factor binding and gene regulation. Genome Biol. 2005; 6(10):R87. PMC: 1257470. DOI: 10.1186/gb-2005-6-10-r87. View

Schreiner P, Heiss G, Tyroler H, Morrisett J, Davis C, Smith R . Race and gender differences in the association of Lp(a) with carotid artery wall thickness. The Atherosclerosis Risk in Communities (ARIC) Study. Arterioscler Thromb Vasc Biol. 1996; 16(3):471-8. DOI: 10.1161/01.atv.16.3.471. View

Matys V, Fricke E, Geffers R, Gossling E, Haubrock M, Hehl R . TRANSFAC: transcriptional regulation, from patterns to profiles. Nucleic Acids Res. 2003; 31(1):374-8. PMC: 165555. DOI: 10.1093/nar/gkg108. View

Thomas M, Seto E . Unlocking the mechanisms of transcription factor YY1: are chromatin modifying enzymes the key?. Gene. 1999; 236(2):197-208. DOI: 10.1016/s0378-1119(99)00261-9. View

Abecasis G, Wigginton J . Handling marker-marker linkage disequilibrium: pedigree analysis with clustered markers. Am J Hum Genet. 2005; 77(5):754-67. PMC: 1271385. DOI: 10.1086/497345. View

White A, Folsom A, Chambless L, Sharret A, Yang K, Conwill D . Community surveillance of coronary heart disease in the Atherosclerosis Risk in Communities (ARIC) Study: methods and initial two years' experience. J Clin Epidemiol. 1996; 49(2):223-33. DOI: 10.1016/0895-4356(95)00041-0. View

10.

Clarke R, Peden J, Hopewell J, Kyriakou T, Goel A, Heath S . Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009; 361(26):2518-28. DOI: 10.1056/NEJMoa0902604. View

11.

Bennet A, Di Angelantonio E, Erqou S, Eiriksdottir G, Sigurdsson G, Woodward M . Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data. Arch Intern Med. 2008; 168(6):598-608. DOI: 10.1001/archinte.168.6.598. View

12.

Carpenter M, Crow R, Steffes M, Rock W, Heilbraun J, Evans G . Laboratory, reading center, and coordinating center data management methods in the Jackson Heart Study. Am J Med Sci. 2004; 328(3):131-44. DOI: 10.1097/00000441-200409000-00001. View

13.

Marcovina S, Albers J, Wijsman E, Zhang Z, Chapman N, Kennedy H . Differences in Lp[a] concentrations and apo[a] polymorphs between black and white Americans. J Lipid Res. 1996; 37(12):2569-85. View

14.

Sandelin A, Alkema W, Engstrom P, Wasserman W, Lenhard B . JASPAR: an open-access database for eukaryotic transcription factor binding profiles. Nucleic Acids Res. 2003; 32(Database issue):D91-4. PMC: 308747. DOI: 10.1093/nar/gkh012. View

15.

Lackner C, Cohen J, Hobbs H . Molecular definition of the extreme size polymorphism in apolipoprotein(a). Hum Mol Genet. 1993; 2(7):933-40. DOI: 10.1093/hmg/2.7.933. View

16.

. The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators. Am J Epidemiol. 1989; 129(4):687-702. View

17.

Deo R, Reich D, Tandon A, Akylbekova E, Patterson N, Waliszewska A . Genetic differences between the determinants of lipid profile phenotypes in African and European Americans: the Jackson Heart Study. PLoS Genet. 2009; 5(1):e1000342. PMC: 2613537. DOI: 10.1371/journal.pgen.1000342. View

18.

Danik J, Rifai N, Buring J, Ridker P . Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women. JAMA. 2006; 296(11):1363-70. DOI: 10.1001/jama.296.11.1363. View

19.

Schreiner P, Morrisett J, Sharrett A, Patsch W, Tyroler H, Wu K . Lipoprotein[a] as a risk factor for preclinical atherosclerosis. Arterioscler Thromb. 1993; 13(6):826-33. DOI: 10.1161/01.atv.13.6.826. View

20.

Mooser V, Scheer D, Marcovina S, Wang J, Guerra R, Cohen J . The Apo(a) gene is the major determinant of variation in plasma Lp(a) levels in African Americans. Am J Hum Genet. 1997; 61(2):402-17. PMC: 1715889. DOI: 10.1086/514851. View