Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease
Using a novel gene chip, investigators identified single-nucleotide polymorphisms (SNPs) from three chromosomal regions, including the LPA locus, that were associated with the risk of coronary disease. Two SNPs in LPA were strongly associated with both the level of Lp(a) lipoprotein and the risk of...
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| Vydáno v: | The New England journal of medicine Ročník 361; číslo 26; s. 2518 - 2528 |
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| Hlavní autoři: | , , , , , , , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
United States
Massachusetts Medical Society
24.12.2009
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| Témata: | |
| ISSN: | 0028-4793, 1533-4406, 1533-4406 |
| On-line přístup: | Získat plný text |
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| Abstract | Using a novel gene chip, investigators identified single-nucleotide polymorphisms (SNPs) from three chromosomal regions, including the
LPA
locus, that were associated with the risk of coronary disease. Two SNPs in
LPA
were strongly associated with both the level of Lp(a) lipoprotein and the risk of coronary disease. After adjustment for the Lp(a) lipoprotein level, the association with the risk of coronary disease was abolished. These findings support a causal role of an increased Lp(a) lipoprotein level in the risk of coronary disease.
Two SNPs in the
LPA
locus were strongly associated with both the level of Lp(a) lipoprotein and the risk of coronary disease. These findings support a causal role of an increased Lp(a) lipoprotein level in the risk of coronary disease.
Genomewide association studies have identified several novel susceptibility loci for coronary artery disease,
1
–
4
but it is likely that only common variants can be detected in this way.
5
,
6
Moreover, loci that are identified with the use of genomewide association studies explain only a small amount of the expected contribution to the risk of coronary disease. The use of arrays of high-density single-nucleotide polymorphisms (SNPs) in candidate genes for cardiovascular disease may help elucidate the genetic contribution to the risk of coronary disease.
A recent genomewide association study showed that a cluster of genes — solute carrier family 22 member . . . |
|---|---|
| AbstractList | 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. Background 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. Methods 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. Results 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. Conclusions 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. Using a novel gene chip, investigators identified single-nucleotide polymorphisms (SNPs) from three chromosomal regions, including the LPA locus, that were associated with the risk of coronary disease. Two SNPs in LPA were strongly associated with both the level of Lp(a) lipoprotein and the risk of coronary disease. After adjustment for the Lp(a) lipoprotein level, the association with the risk of coronary disease was abolished. These findings support a causal role of an increased Lp(a) lipoprotein level in the risk of coronary disease. Two SNPs in the LPA locus were strongly associated with both the level of Lp(a) lipoprotein and the risk of coronary disease. These findings support a causal role of an increased Lp(a) lipoprotein level in the risk of coronary disease. Genomewide association studies have identified several novel susceptibility loci for coronary artery disease, 1 – 4 but it is likely that only common variants can be detected in this way. 5 , 6 Moreover, loci that are identified with the use of genomewide association studies explain only a small amount of the expected contribution to the risk of coronary disease. The use of arrays of high-density single-nucleotide polymorphisms (SNPs) in candidate genes for cardiovascular disease may help elucidate the genetic contribution to the risk of coronary disease. A recent genomewide association study showed that a cluster of genes — solute carrier family 22 member . . . 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.BACKGROUNDAn 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.METHODSWe 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.RESULTSThree 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.CONCLUSIONSWe 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. |
| Author | Barlera, Simona Rust, Stephan Seedorf, Udo Malarstig, Anders Franzosi, Maria Grazia Parish, Sarah Heath, Simon C Watkins, Hugh de Faire, Ulf Kyriakou, Theodosios Silveira, Angela Leander, Karin Green, Fiona R Gigante, Bruna Peden, John F Bennett, Derrick Clarke, Robert Lathrop, Mark Hopewell, Jemma C Farrall, Martin Hamsten, Anders Goel, Anuj Collins, Rory |
| Author_xml | – sequence: 1 givenname: Robert surname: Clarke fullname: Clarke, Robert – sequence: 2 givenname: John F surname: Peden fullname: Peden, John F – sequence: 3 givenname: Jemma C surname: Hopewell fullname: Hopewell, Jemma C – sequence: 4 givenname: Theodosios surname: Kyriakou fullname: Kyriakou, Theodosios – sequence: 5 givenname: Anuj surname: Goel fullname: Goel, Anuj – sequence: 6 givenname: Simon C surname: Heath fullname: Heath, Simon C – sequence: 7 givenname: Sarah surname: Parish fullname: Parish, Sarah – sequence: 8 givenname: Simona surname: Barlera fullname: Barlera, Simona – sequence: 9 givenname: Maria Grazia surname: Franzosi fullname: Franzosi, Maria Grazia – sequence: 10 givenname: Stephan surname: Rust fullname: Rust, Stephan – sequence: 11 givenname: Derrick surname: Bennett fullname: Bennett, Derrick – sequence: 12 givenname: Angela surname: Silveira fullname: Silveira, Angela – sequence: 13 givenname: Anders surname: Malarstig fullname: Malarstig, Anders – sequence: 14 givenname: Fiona R surname: Green fullname: Green, Fiona R – sequence: 15 givenname: Mark surname: Lathrop fullname: Lathrop, Mark – sequence: 16 givenname: Bruna surname: Gigante fullname: Gigante, Bruna – sequence: 17 givenname: Karin surname: Leander fullname: Leander, Karin – sequence: 18 givenname: Ulf surname: de Faire fullname: de Faire, Ulf – sequence: 19 givenname: Udo surname: Seedorf fullname: Seedorf, Udo – sequence: 20 givenname: Anders surname: Hamsten fullname: Hamsten, Anders – sequence: 21 givenname: Rory surname: Collins fullname: Collins, Rory – sequence: 22 givenname: Hugh surname: Watkins fullname: Watkins, Hugh – sequence: 23 givenname: Martin surname: Farrall fullname: Farrall, Martin |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/20032323$$D View this record in MEDLINE/PubMed http://kipublications.ki.se/Default.aspx?queryparsed=id:119799716$$DView record from Swedish Publication Index (Karolinska Institutet) |
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| Snippet | Using a novel gene chip, investigators identified single-nucleotide polymorphisms (SNPs) from three chromosomal regions, including the
LPA
locus, that were... 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... Background An increased level of Lp(a) lipoprotein has been identified as a risk factor for coronary artery disease that is highly heritable. The genetic... |
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| SubjectTerms | Apolipoproteins Cardiovascular disease Case-Control Studies Coronary Disease - blood Coronary Disease - genetics Coronary vessels Genes Genetic Markers Genetic Predisposition to Disease Genome-Wide Association Study Genotype Humans Kringles - genetics Likelihood Functions Lipoprotein(a) - blood Lipoprotein(a) - chemistry Lipoprotein(a) - genetics Lipoproteins Myocardial Infarction - genetics Oligonucleotide Array Sequence Analysis Polymorphism, Single Nucleotide Regression Analysis Risk Factors Systematic review |
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| Title | Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease |
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