Polymorphisms associated with cholesterol and risk of cardiovascular events

被引:539
作者
Kathiresan, Sekar [1 ,4 ,8 ,9 ]
Melander, Olle [10 ]
Anevski, Dragi [11 ,14 ]
Guiducci, Candace [8 ,9 ]
Burtt, Noel P. [8 ,9 ]
Roos, Charlotta [11 ]
Hirschhorn, Joel N. [5 ,6 ,7 ,8 ,9 ]
Berglund, Goran [12 ]
Hedblad, Bo [13 ]
Groop, Leif [11 ,15 ]
Altshuler, David M. [2 ,3 ,4 ,6 ,8 ,9 ]
Newton-Cheh, Christopher [1 ,4 ,8 ,9 ]
Orho-Melander, Marju [11 ]
机构
[1] Massachusetts Gen Hosp, Cardiovasc Dis Prevent Ctr, Div Cardiol, Boston, MA 02114 USA
[2] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA
[3] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA
[4] Harvard Univ, Sch Med, Dept Med, Boston, MA USA
[5] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA
[6] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA
[7] Childrens Hosp, Div Endocrinol & Genet, Boston, MA 02115 USA
[8] MIT, Broad Inst, Cambridge, MA 02139 USA
[9] Harvard Univ, Cambridge, MA 02138 USA
[10] Lund Univ, Malmo Univ Hosp, Dept Clin Sci Hypertens & Cardiovasc Dis, Malmo, Sweden
[11] Lund Univ, Malmo Univ Hosp, Dept Endocrinol & Diabet, Malmo, Sweden
[12] Lund Univ, Malmo Univ Hosp, Dept Internal Med, Malmo, Sweden
[13] Lund Univ, Malmo Univ Hosp, Dept Epidemiol Res, Malmo, Sweden
[14] Chalmers Univ Technol, S-41296 Gothenburg, Sweden
[15] Helsinki Univ Hosp, Helsinki, Finland
关键词
D O I
10.1056/NEJMoa0706728
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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页码:1240 / 1249
页数:10
相关论文
共 36 条
[1]  
ALTSHULER D, 2007, WHOLE GENOME SCANE T
[2]   Polymorphism in APOB associated with increased low-density lipoprotein levels in both genders in the general population [J].
Benn, M ;
Nordestgaard, BG ;
Jensen, JS ;
Grande, P ;
Sillesen, H ;
Tybjærg-Hansen, A .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2005, 90 (10) :5797-5803
[3]   DESIGN AND FEASIBILITY [J].
BERGLUND, G ;
ELMSTAHL, S ;
JANZON, L ;
LARSSON, SA .
JOURNAL OF INTERNAL MEDICINE, 1993, 233 (01) :45-51
[4]   Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment - Individual patient meta-analysis of 13,677 subjects [J].
Boekholdt, SM ;
Sacks, FM ;
Jukema, JW ;
Shepherd, J ;
Freeman, DJ ;
McMahon, AD ;
Cambien, F ;
Nicaud, V ;
de Grooth, GJ ;
Talmud, PJ ;
Humphries, SE ;
Miller, GJ ;
Eiriksdottir, G ;
Gudnason, V ;
Kauma, H ;
Kakko, S ;
Savolainen, MJ ;
Arca, M ;
Montali, A ;
Liu, S ;
Lanz, HJ ;
Zwinderman, AH ;
Kuivenhoven, JA ;
Kastelein, JJP .
CIRCULATION, 2005, 111 (03) :278-287
[5]   Association and linkage of LDLR gene variation with variation in plasma low density lipoprotein cholesterol [J].
Boright, AP ;
Connelly, PW ;
Brunt, JH ;
Morgan, K ;
Hegele, RA .
JOURNAL OF HUMAN GENETICS, 1998, 43 (03) :153-159
[6]   Biomedicine - Lowering LDL - Not only how low, but how long? [J].
Brown, MS ;
Goldstein, JL .
SCIENCE, 2006, 311 (5768) :1721-1723
[7]   Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) [J].
Cleeman, JI ;
Grundy, SM ;
Becker, D ;
Clark, LT ;
Cooper, RS ;
Denke, MA ;
Howard, WJ ;
Hunninghake, DB ;
Illingworth, DR ;
Luepker, RV ;
McBride, P ;
McKenney, JM ;
Pasternak, RC ;
Stone, NJ ;
Van Horn, L ;
Brewer, HB ;
Ernst, ND ;
Gordon, D ;
Levy, D ;
Rifkind, B ;
Rossouw, JE ;
Savage, P ;
Haffner, SM ;
Orloff, DG ;
Proschan, MA ;
Schwartz, JS ;
Sempos, CT ;
Shero, ST ;
Murray, EZ .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2001, 285 (19) :2486-2497
[8]   Sequence variations in PCSK9, low LDL, and protection against coronary heart disease [J].
Cohen, JC ;
Boerwinkle, E ;
Mosley, TH ;
Hobbs, HH .
NEW ENGLAND JOURNAL OF MEDICINE, 2006, 354 (12) :1264-1272
[9]   Use and misuse of the receiver operating characteristic curve in risk prediction [J].
Cook, Nancy R. .
CIRCULATION, 2007, 115 (07) :928-935
[10]  
Cooper GR, 1997, JAMA-J AM MED ASSOC, V278, P478