Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease
Top Cited Papers
- 24 December 2009
- journal article
- research article
- Published by Massachusetts Medical Society in New England Journal of Medicine
- Vol. 361 (26), 2518-2528
- https://doi.org/10.1056/nejmoa0902604
Abstract
An increased level of Lp(a) lipoprotein has been identified as a risk factor for coronary artery disease that is highly heritable. The genetic determinants of the Lp(a) lipoprotein level and their relevance for the risk of coronary disease are incompletely understood. We used a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2100 candidate genes to test for associations in 3145 case subjects with coronary disease and 3352 control subjects. Replication was tested in three independent populations involving 4846 additional case subjects with coronary disease and 4594 control subjects. Three chromosomal regions (6q26–27, 9p21, and 1p13) were strongly associated with the risk of coronary disease. The LPA locus on 6q26–27 encoding Lp(a) lipoprotein had the strongest association. We identified a common variant (rs10455872) at the LPA locus with an odds ratio for coronary disease of 1.70 (95% confidence interval [CI], 1.49 to 1.95) and another independent variant (rs3798220) with an odds ratio of 1.92 (95% CI, 1.48 to 2.49). Both variants were strongly associated with an increased level of Lp(a) lipoprotein, a reduced copy number in LPA (which determines the number of kringle IV–type 2 repeats), and a small Lp(a) lipoprotein size. Replication studies confirmed the effects of both variants on the Lp(a) lipoprotein level and the risk of coronary disease. A meta-analysis showed that with a genotype score involving both LPA SNPs, the odds ratios for coronary disease were 1.51 (95% CI, 1.38 to 1.66) for one variant and 2.57 (95% CI, 1.80 to 3.67) for two or more variants. After adjustment for the Lp(a) lipoprotein level, the association between the LPA genotype score and the risk of coronary disease was abolished. We identified two LPA variants that were strongly associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. Our findings provide support for a causal role of Lp(a) lipoprotein in coronary disease.Keywords
This publication has 40 references indexed in Scilit:
- Lipoprotein(a) Concentration and the Risk of Coronary Heart Disease, Stroke, and Nonvascular MortalityJama-Journal Of The American Medical Association, 2009
- Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6qJournal of Lipid Research, 2009
- Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapyAtherosclerosis, 2009
- Determination of lipoprotein(a) kringle repeat number from genomic DNA: copy number variation genotyping using qPCRJournal of Lipid Research, 2009
- Common variants at 30 loci contribute to polygenic dyslipidemiaNature Genetics, 2008
- Genomewide Association Analysis of Coronary Artery DiseaseNew England Journal of Medicine, 2007
- A Common Allele on Chromosome 9 Associated with Coronary Heart DiseaseScience, 2007
- Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controlsNature, 2007
- A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility VariantsScience, 2007
- Multiple QTL influence the serum Lp(a) concentration: a genome-wide linkage screen in the PROCARDIS studyEuropean Journal of Human Genetics, 2006