Polymorphisms associated with cholesterol and risk of cardiovascular events
Journal article, 2008

Background: Common single-nucleotide polymorphisms (SNPs) that are associated with blood low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol modestly affect lipid levels. We tested the hypothesis that a combination of such SNPs contributes to the risk of cardiovascular disease. Methods: We studied SNPs at nine loci in 5414 subjects from the cardiovascular cohort of the Malmo Diet and Cancer Study. We first validated the association between SNPs and either LDL or HDL cholesterol and subsequently created a genotype score on the basis of the number of unfavorable alleles. We used Cox proportional-hazards models to determine the time to the first cardiovascular event in relation to the genotype score. Results: All nine SNPs showed replication of an association with levels of either LDL or HDL cholesterol. With increasing genotype scores, the level of LDL cholesterol increased from 152 mg to 171 mg per deciliter (3.9 to 4.4 mmol per liter), whereas HDL cholesterol decreased from 60 mg to 51 mg per deciliter (1.6 to 1.3 mmol per liter). During follow-up (median, 10.6 years), 238 subjects had a first cardiovascular event. The genotype score was associated with incident cardiovascular disease in models adjusted for covariates including baseline lipid levels (P<0.001). The use of the genotype score did not improve the clinical risk prediction, as assessed by the C statistic. However, there was a significant improvement in risk classification with the use of models that included the genotype score, as compared with those that did not include the genotype score. Conclusions: A genotype score of nine validated SNPs that are associated with modulation in levels of LDL or HDL cholesterol was an independent risk factor for incident cardiovascular disease. The score did not improve risk discrimination but did modestly improve clinical risk reclassification for individual subjects beyond standard clinical factors.

DENSITY-LIPOPROTEIN CHOLESTEROL

MALMO

ARTERY-DISEASE

GENERAL-POPULATION

TRIGLYCERIDES

CONTRIBUTES

GENOME

CURVE

LOCI

CORONARY-HEART-DISEASE

Author

S. Kathiresan

Massachusetts General Hospital

Harvard Medical School

Harvard University

O. Melander

Skåne University Hospital

Dragi Anevski

Chalmers, Mathematical Sciences, Mathematical Statistics

University of Gothenburg

C. Guiducci

Harvard University

N. P. Burtt

Harvard University

C. Roos

Skåne University Hospital

J. N. Hirschhorn

Children's Hospital Boston

Harvard University

Harvard Medical School

G. Berglund

Skåne University Hospital

B. Hedblad

Skåne University Hospital

L. Groop

Skåne University Hospital

Helsinki University Central Hospital

D. Altshuler

Harvard University

Harvard Medical School

Massachusetts General Hospital

C. Newton-Cheh

Harvard Medical School

Harvard University

Massachusetts General Hospital

M. Orho-Melander

Skåne University Hospital

New England Journal of Medicine

0028-4793 (ISSN) 1533-4406 (eISSN)

Vol. 358 12 1240-1249

Subject Categories

Cardiac and Cardiovascular Systems

DOI

10.1056/NEJMoa0706728

More information

Latest update

5/14/2018