Polymorphisms associated with cholesterol and risk of cardiovascular events.
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 Malmö 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.
Kathiresan
Sekar
S
Cardiovascular Disease Prevention Center, Cardiology Division, Massachusetts General Hospital, MA 02114, USA. skathiresan@partners.org
Melander
Olle
O
Anevski
Dragi
D
Guiducci
Candace
C
Burtt
Noël P
NP
Roos
Charlotta
C
Hirschhorn
Joel N
JN
Berglund
Göran
G
Hedblad
Bo
B
Groop
Leif
L
Altshuler
David M
DM
Newton-Cheh
Christopher
C
Orho-Melander
Marju
M
D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics*; D003327:Coronary Disease / Q000235:genetics / Q000401:mortality; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009203:Myocardial Infarction / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012372:ROC Curve; D012307:Risk Factors; D020521:Stroke / Q000235:genetics
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL