[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.197.66.254. Please contact the publisher to request reinstatement.
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Download PDF
Table 1. Validation of Predefined Risk Genotype Comparisons in Cases vs Controls
Image description not available.
Table 2. Genotype Frequencies and P Values in Cases With Acute Coronary Syndrome and Controls
Image description not available.
Table 3. Characteristics of 1461 White Participants Genotyped for 85 Genetic Variants*
Image description not available.
1.
Marenberg ME, Risch N, Berkman LF, Floderus B, de Faire U. Genetic susceptibility to death from coronary heart disease in a study of twins.  N Engl J Med. 1994;330:1041-1046PubMedArticle
2.
Scheuner MT. Clinical application of genetic risk assessment strategies for coronary artery disease: genotypes, phenotypes, and family history.  Prim Care. 2004;31:711-737, xi-xiiPubMedArticle
3.
Casas JPCJ, Miller GJ, Hingorani AD, Humphries SE. Investigating the genetic determinants of cardiovascular disease using candidate genes and meta-analysis of association studies.  Ann Hum Genet. 2006;70:145-169PubMedArticle
4.
Morgan TM, Coffey CS, Krumholz HM. Overestimation of genetic risks owing to small sample sizes in cardiovascular studies.  Clin Genet. 2003;6 4:7-17PubMedArticle
5.
Yamada Y. Identification of genetic factors and development of genetic risk diagnosis systems for cardiovascular diseases and stroke.  Circ J. 2006;70:1240-1248PubMedArticle
6.
Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG. Replication validity of genetic association studies.  Nat Genet. 2001;29:306-309PubMedArticle
7.
The International HapMap Consortium.  The International HapMap Project.  Nature. 2003;426:789-796PubMedArticle
8.
Lutucuta S, Ballantyne CM, Elghannam H, Gotto AM Jr, Marian AJ. Novel polymorphisms in promoter region of ATP binding cassette transporter gene and plasma lipids, severity, progression, and regression of coronary atherosclerosis and response to therapy.  Circ Res. 2001;88:969-973PubMedArticle
9.
Zwarts KY, Clee SM, Zwinderman AH.  et al.  ABCA1 regulatory variants influence coronary artery disease independent of effects on plasma lipid levels.  Clin Genet. 2002;61:115-125PubMedArticle
10.
Clee SM, Zwinderman AH, Engert JC.  et al.  Common genetic variation in ABCA1 is associated with altered lipoprotein levels and a modified risk for coronary artery disease.  Circulation. 2001;103:1198-1205PubMedArticle
11.
Tregouet DA, Ricard S, Nicaud V.  et al.  In-depth haplotype analysis of ABCA1 gene polymorphisms in relation to plasma ApoA1 levels and myocardial infarction.  Arterioscler Thromb Vasc Biol. 2004;24:775-781PubMedArticle
12.
Tobin MD, Braund PS, Burton PR.  et al.  Genotypes and haplotypes predisposing to myocardial infarction: a multilocus case-control study.  Eur Heart J. 2004;25:459-467PubMedArticle
13.
Zee RY, Cook NR, Reynolds R, Cheng S, Ridker PM. Haplotype analysis of the beta2 adrenergic receptor gene and risk of myocardial infarction in humans.  Genetics. 2005;169:1583-1587PubMedArticle
14.
Higashi K, Ishikawa T, Ito T, Yonemura A, Shige H, Nakamura H. Association of a genetic variation in the beta 3-adrenergic receptor gene with coronary heart disease among Japanese.  Biochem Biophys Res Commun. 1997;232:728-730PubMedArticle
15.
Sethi AA, Nordestgaard BG, Tybjaerg-Hansen A. Angiotensinogen gene polymorphism, plasma angiotensinogen, and risk of hypertension and ischemic heart disease: a meta-analysis.  Arterioscler Thromb Vasc Biol. 2003;23:1269-1275PubMedArticle
16.
Fatini C, Abbate R, Pepe G.  et al.  Searching for a better assessment of the individual coronary risk profile: the role of angiotensin-converting enzyme, angiotensin II type 1 receptor and angiotensinogen gene polymorphisms.  Eur Heart J. 2000;21:633-638PubMedArticle
17.
Helgadottir A, Manolescu A, Thorleifsson G.  et al.  The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke.  Nat Genet. 2004;36:233-239PubMedArticle
18.
Wang XL, Liu SX, McCredie RM, Wilcken DE. Polymorphisms at the 5′-end of the apolipoprotein AI gene and severity of coronary artery disease.  J Clin Invest. 1996;98:372-377PubMedArticle
19.
Reguero JR, Cubero GI, Batalla A.  et al.  Apolipoprotein A1 gene polymorphisms and risk of early coronary disease.  Cardiology. 1998;90:231-235PubMedArticle
20.
Wilson PW, Schaefer EJ, Larson MG, Ordovas JM. Apolipoprotein E alleles and risk of coronary disease: a meta-analysis.  Arterioscler Thromb Vasc Biol. 1996;16:1250-1255PubMedArticle
21.
Lambert JC, Brousseau T, Defosse V.  et al.  Independent association of an APOE gene promoter polymorphism with increased risk of myocardial infarction and decreased APOE plasma concentrations-the ECTIM study.  Hum Mol Genet. 2000;9:57-61PubMedArticle
22.
Aoki S, Mukae S, Itoh S.  et al.  The genetic factor in acute myocardial infarction with hypertension.  Jpn Circ J. 2001;65:621-626PubMedArticle
23.
Zee RY, Cook NR, Cheng S.  et al.  Threonine for alanine substitution in the eotaxin (CCL11) gene and the risk of incident myocardial infarction.  Atherosclerosis. 2004;175:91-94PubMedArticle
24.
Ortlepp JR, Vesper K, Mevissen V.  et al.  Chemokine receptor (CCR2) genotype is associated with myocardial infarction and heart failure in patients under 65 years of age.  J Mol Med. 2003;81:363-367PubMedArticle
25.
González P, Alvarez R, Batalla A.  et al.  Genetic variation at the chemokine receptors CCR5/CCR2 in myocardial infarction.  Genes Immun. 2001;2:191-195PubMedArticle
26.
Hubacek JA, Rothe G, Pit'ha J.  et al.  C(−260)→T polymorphism in the promoter of the CD14 monocyte receptor gene as a risk factor for myocardial infarction.  Circulation. 1999;99:3218-3220PubMedArticle
27.
Kuivenhoven JA, Jukema JW, Zwinderman AH.  et al. the Regression Growth Evaluation Statin Study Group.  The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis.  N Engl J Med. 1998;338:86-93PubMedArticle
28.
Klerkx AH, Tanck MW, Kastelein JJ.  et al.  Haplotype analysis of the CETP gene: not TaqIB, but the closely linked −629C→A polymorphism and a novel promoter variant are independently associated with CETP concentration.  Hum Mol Genet. 2003;12:111-123PubMedArticle
29.
Eriksson AL, Skrtic S, Niklason A.  et al.  Association between the low activity genotype of catechol-O-methyltransferase and myocardial infarction in a hypertensive population.  Eur Heart J. 2004;25:386-391PubMedArticle
30.
Niessner A, Marculescu R, Haschemi A.  et al.  Opposite effects of CX3CR1 receptor polymorphisms V249I and T280M on the development of acute coronary syndrome: a possible implication of fractalkine in inflammatory activation.  Thromb Haemost. 2005;93:949-954PubMed
31.
McDermott DH, Halcox JP, Schenke WH.  et al.  Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis.  Circ Res. 2001;89:401-407PubMedArticle
32.
Patel S, Steeds R, Channer K, Samani NJ. Analysis of promoter region polymorphism in the aldosterone synthase gene (CYP11B2) as a risk factor for myocardial infarction.  Am J Hypertens. 2000;13:134-139PubMedArticle
33.
Hautanen A, Toivanen P, Manttari M.  et al.  Joint effects of an aldosterone synthase (CYP11B2) gene polymorphism and classic risk factors on risk of myocardial infarction.  Circulation. 1999;100:2213-2218PubMedArticle
34.
Yasar U, Bennet AM, Eliasson E.  et al.  Allelic variants of cytochromes P450 2C modify the risk for acute myocardial infarction.  Pharmacogenetics. 2003;13:715-720PubMedArticle
35.
Funk M, Endler G, Freitag R.  et al.  CYP2C9*2 and CYP2C9*3 alleles confer a lower risk for myocardial infarction.  Clin Chem. 2004;50:2395-2398PubMedArticle
36.
Endler G, Mannhalter C, Sunder-Plassmann H.  et al.  The K121Q polymorphism in the plasma cell membrane glycoprotein 1 gene predisposes to early myocardial infarction.  J Mol Med. 2002;80:791-795PubMedArticle
37.
Schuit SC, Oei HH, Witteman JC.  et al.  Estrogen receptor alpha gene polymorphisms and risk of myocardial infarction.  JAMA. 2004;291:2969-2977PubMedArticle
38.
Shearman AM, Cupples LA, Demissie S.  et al.  Association between estrogen receptor alpha gene variation and cardiovascular disease.  JAMA. 2003;290:2263-2270PubMedArticle
39.
Endler G, Mannhalter C, Sunder-Plassmann H.  et al.  Homozygosity for the C→T polymorphism at nucleotide 46 in the 5′ untranslated region of the factor XII gene protects from development of acute coronary syndrome.  Br J Haematol. 2001;115:1007-1009PubMedArticle
40.
Endler G, Mannhalter C. Polymorphisms in coagulation factor genes and their impact on arterial and venous thrombosis.  Clin Chim Acta. 2003;330:31-55PubMedArticle
41.
Rosendaal FR, Siscovick DS, Schwartz SM, Psaty BM, Raghunathan TE, Vos HL. A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women.  Blood. 1997;90:1747-1750PubMed
42.
Girelli D, Russo C, Ferraresi P.  et al.  Polymorphisms in the factor VII gene and the risk of myocardial infarction in patients with coronary artery disease.  N Engl J Med. 2000;343:774-780PubMedArticle
43.
Boekholdt SM, Bijsterveld NR, Moons AH, Levi M, Buller HR, Peters RJ. Genetic variation in coagulation and fibrinolytic proteins and their relation with acute myocardial infarction: a systematic review.  Circulation. 2001;104:3063-3068PubMedArticle
44.
Yamada Y, Izawa H, Ichihara S.  et al.  Prediction of the risk of myocardial infarction from polymorphisms in candidate genes.  N Engl J Med. 2002;347:1916-1923PubMedArticle
45.
Kenny D, Muckian C, Fitzgerald DJ, Cannon CP, Shields DC. Platelet glycoprotein Ib alpha receptor polymorphisms and recurrent ischaemic events in acute coronary syndrome patients.  J Thromb Thrombolysis. 2002;13:13-19PubMedArticle
46.
Douglas H, Michaelides K, Gorog DA.  et al.  Platelet membrane glycoprotein Ibalpha gene −5T/C Kozak sequence polymorphism as an independent risk factor for the occurrence of coronary thrombosis.  Heart. 2002;87:70-74PubMedArticle
47.
Lin RC, Wang XL, Morris BJ. Association of coronary artery disease with glucocorticoid receptor N363S variant.  Hypertension. 2003;41:404-407PubMedArticle
48.
Hetet G, Elbaz A, Gariepy J.  et al.  Association studies between haemochromatosis gene mutations and the risk of cardiovascular diseases.  Eur J Clin Invest. 2001;31:382-388PubMedArticle
49.
Yamada S, Akita H, Kanazawa K.  et al.  T102C polymorphism of the serotonin (5-HT) 2A receptor gene in patients with non-fatal acute myocardial infarction.  Atherosclerosis. 2000;150:143-148PubMedArticle
50.
Jiang H, Klein RM, Niederacher D.  et al.  C/T polymorphism of the intercellular adhesion molecule-1 gene (exon 6, codon 469): a risk factor for coronary heart disease and myocardial infarction.  Int J Cardiol. 2002;84:171-177PubMedArticle
51.
Momiyama Y, Hirano R, Taniguchi H, Nakamura H, Ohsuzu F. Effects of interleukin-1 gene polymorphisms on the development of coronary artery disease associated with Chlamydia pneumoniae infection.  J Am Coll Cardiol. 2001;38:712-717PubMedArticle
52.
Georges JL, Loukaci V, Poirier O.  et al. Etude Cas-Temoin de l'Infarctus du Myocarde.  Interleukin-6 gene polymorphisms and susceptibility to myocardial infarction: the ECTIM study.  J Mol Med. 2001;79:300-305PubMedArticle
53.
Jenny NS, Tracy RP, Ogg MS.  et al.  In the elderly, interleukin-6 plasma levels and the −174G>C polymorphism are associated with the development of cardiovascular disease.  Arterioscler Thromb Vasc Biol. 2002;22:2066-2071PubMedArticle
54.
Baroni MG, D'Andrea MP, Montali A.  et al.  A common mutation of the insulin receptor substrate-1 gene is a risk factor for coronary artery disease.  Arterioscler Thromb Vasc Biol. 1999;19:2975-2980PubMedArticle
55.
Santoso S, Kunicki TJ, Kroll H, Haberbosch W, Gardemann A. Association of the platelet glycoprotein Ia C807T gene polymorphism with nonfatal myocardial infarction in younger patients.  Blood. 1999;93:2449-2453PubMed
56.
Samara WM, Gurbel PA. The role of platelet receptors and adhesion molecules in coronary artery disease.  Coron Artery Dis. 2003;14:65-79PubMedArticle
57.
Zambon A, Deeb SS, Pauletto P, Crepaldi G, Brunzell JD. Hepatic lipase: a marker for cardiovascular disease risk and response to therapy.  Curr Opin Lipidol. 2003;14:179-189PubMedArticle
58.
Ji J, Herbison CE, Mamotte CD, Burke V, Taylor RR, van Bockxmeer FM. Hepatic lipase gene −514 C/T polymorphism and premature coronary heart disease.  J Cardiovasc Risk. 2002;9:105-113PubMedArticle
59.
Hokanson JE. Functional variants in the lipoprotein lipase gene and risk cardiovascular disease.  Curr Opin Lipidol. 1999;10:393-399PubMedArticle
60.
Schulz S, Schagdarsurengin U, Greiser P.  et al.  The LDL receptor-related protein (LRP1/A2MR) and coronary atherosclerosis–novel genomic variants and functional consequences.  Hum Mutat. 2002;20:404PubMedArticle
61.
PROCARDIS Consortium.  A trio family study showing association of the lymphotoxin-alpha N26 (804A) allele with coronary artery disease.  Eur J Hum Genet. 2004;12:770-774PubMedArticle
62.
Ozaki K, Ohnishi Y, Iida A.  et al.  Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction.  Nat Genet. 2002;32:650-654PubMedArticle
63.
Herrmann SM, Whatling C, Brand E.  et al.  Polymorphisms of the human matrix gla protein (MGP) gene, vascular calcification, and myocardial infarction.  Arterioscler Thromb Vasc Biol. 2000;20:2386-2393PubMedArticle
64.
Humphries SE, Martin S, Cooper J, Miller G. Interaction between smoking and the stromelysin-1 (MMP3) gene 5A/6A promoter polymorphism and risk of coronary heart disease in healthy men.  Ann Hum Genet. 2002;66:343-352PubMedArticle
65.
Lamblin N, Bauters C, Hermant X, Lablanche JM, Helbecque N, Amouyel P. Polymorphisms in the promoter regions of MMP-2, MMP-3, MMP-9 and MMP-12 genes as determinants of aneurysmal coronary artery disease.  J Am Coll Cardiol. 2002;40:43-48PubMedArticle
66.
Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG. MTHFR 677C→T polymorphism and risk of coronary heart disease: a meta-analysis.  JAMA. 2002;288:2023-2031PubMedArticle
67.
Ledmyr H, McMahon AD, Ehrenborg E.  et al.  The microsomal triglyceride transfer protein gene-493T variant lowers cholesterol but increases the risk of coronary heart disease.  Circulation. 2004;109:2279-2284PubMedArticle
68.
Juo SH, Han Z, Smith JD, Colangelo L, Liu K. Common polymorphism in promoter of microsomal triglyceride transfer protein gene influences cholesterol, ApoB, and triglyceride levels in young African American men: results from the coronary artery risk development in young adults (CARDIA) study.  Arterioscler Thromb Vasc Biol. 2000;20:1316-1322PubMedArticle
69.
Hyndman ME, Bridge PJ, Warnica JW, Fick G, Parsons HG. Effect of heterozygosity for the methionine synthase 2756 A→G mutation on the risk for recurrent cardiovascular events.  Am J Cardiol. 2000;86:1144-1146, A1149PubMedArticle
70.
Gruchala M, Ciecwierz D, Wasag B.  et al.  Association of the ScaI atrial natriuretic peptide gene polymorphism with nonfatal myocardial infarction and extent of coronary artery disease.  Am Heart J. 2003;145:125-131PubMedArticle
71.
Tatsuguchi M, Furutani M, Hinagata J.  et al.  Oxidized LDL receptor gene (OLR1) is associated with the risk of myocardial infarction.  Biochem Biophys Res Commun. 2003;303:247-250PubMedArticle
72.
Gardemann A, Mages P, Katz N, Tillmanns H, Haberbosch W. The p22 phox A640G gene polymorphism but not the C242T gene variation is associated with coronary heart disease in younger individuals.  Atherosclerosis. 1999;145:315-323PubMedArticle
73.
Inoue N, Kawashima S, Kanazawa K, Yamada S, Akita H, Yokoyama M. Polymorphism of the NADH/NADPH oxidase p22-phox gene in patients with coronary artery disease.  Circulation. 1998;97:135-137PubMedArticle
74.
Wenzel K, Baumann G, Felix SB. The homozygous combination of Leu125Val and Ser563Asn polymorphisms in the PECAM1 (CD31) gene is associated with early severe coronary heart disease.  Hum Mutat. 1999;14:545PubMedArticle
75.
Andreotti F, Porto I, Crea F, Maseri A. Inflammatory gene polymorphisms and ischaemic heart disease: review of population association studies.  Heart. 2002;87:107-112PubMedArticle
76.
Durrington PN, Mackness B, Mackness MI. Paraoxonase and atherosclerosis.  Arterioscler Thromb Vasc Biol. 2001;21:473-480PubMedArticle
77.
Sanghera DK, Aston CE, Saha N, Kamboh MI. DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease.  Am J Hum Genet. 1998;62:36-44PubMedArticle
78.
Ridker PM, Cook NR, Cheng S.  et al.  Alanine for proline substitution in the peroxisome proliferator-activated receptor gamma-2 (PPARG2) gene and the risk of incident myocardial infarction.  Arterioscler Thromb Vasc Biol. 2003;23:859-863PubMedArticle
79.
Cipollone F, Toniato E, Martinotti S.  et al.  A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke.  JAMA. 2004;291:2221-2228PubMedArticle
80.
Ye L, Miki T, Nakura J.  et al.  Association of a polymorphic variant of the Werner helicase gene with myocardial infarction in a Japanese population.  Am J Med Genet. 1997;68:494-498PubMedArticle
81.
Herrmann SM, Ricard S, Nicaud V.  et al.  The P-selectin gene is highly polymorphic: reduced frequency of the Pro715 allele carriers in patients with myocardial infarction.  Hum Mol Genet. 1998;7:1277-1284PubMedArticle
82.
Moatti D, Seknadji P, Galand C.  et al.  Polymorphisms of the tissue factor pathway inhibitor (TFPI) gene in patients with acute coronary syndromes and in healthy subjects: impact of the V264M substitution on plasma levels of TFPI.  Arterioscler Thromb Vasc Biol. 1999;19:862-869PubMedArticle
83.
Chao TH, Li YH, Chen JH.  et al.  Relation of thrombomodulin gene polymorphisms to acute myocardial infarction in patients <or =50 years of age.  Am J Cardiol. 2004;93:204-207PubMedArticle
84.
Doggen CJ, Kunz G, Rosendaal FR.  et al.  A mutation in the thrombomodulin gene, 127G to A coding for Ala25Thr, and the risk of myocardial infarction in men.  Thromb Haemost. 1998;80:743-748PubMed
85.
Wu KK, Aleksic N, Ahn C, Boerwinkle E, Folsom AR, Juneja H. Thrombomodulin Ala455Val polymorphism and risk of coronary heart disease.  Circulation. 2001;103:1386-1389PubMedArticle
86.
Topol EJ, McCarthy J, Gabriel S.  et al.  Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction.  Circulation. 2001;104:2641-2644PubMedArticle
87.
Boekholdt SM, Trip MD, Peters RJ.  et al.  Thrombospondin-2 polymorphism is associated with a reduced risk of premature myocardial infarction.  Arterioscler Thromb Vasc Biol. 2002;22:e24-e27PubMedArticle
88.
Webb KE, Martin JF, Hamsten A.  et al.  Polymorphisms in the thrombopoietin gene are associated with risk of myocardial infarction at a young age.  Atherosclerosis. 2001;154:703-711PubMedArticle
89.
Kolek MJ, Carlquist JF, Muhlestein JB.  et al.  Toll-like receptor 4 gene Asp299Gly polymorphism is associated with reductions in vascular inflammation, angiographic coronary artery disease, and clinical diabetes.  Am Heart J. 2004;148:1034-1040PubMedArticle
90.
Padovani JC, Pazin-Filho A, Simoes MV, Marin-Neto JA, Zago MA, Franco RF. Gene polymorphisms in the TNF locus and the risk of myocardial infarction.  Thromb Res. 2000;100:263-269PubMedArticle
91.
Poirier O, Nicaud V, Gariepy J.  et al.  Polymorphism R92Q of the tumour necrosis factor receptor 1 gene is associated with myocardial infarction and carotid intima-media thickness–the ECTIM, AXA, EVA and GENIC Studies.  Eur J Hum Genet. 2004;12:213-219PubMedArticle
92.
Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined—a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction.  J Am Coll Cardiol. 2000;36:959-969PubMedArticle
93.
Braunwald E. Unstable angina: a classification.  Circulation. 1989;80:410-414PubMedArticle
94.
Yan J, Feng J, Hosono S, Sommer SS. Assessment of multiple displacement amplification in molecular epidemiology.  Biotechniques. 2004;37:136-138, 140-133PubMed
95.
Dean FB, Hosono S, Fang L.  et al.  Comprehensive human genome amplification using multiple displacement amplification.  Proc Natl Acad Sci U S A. 2002;99:5261-5266PubMedArticle
96.
Jurinke C, van den Boom D, Cantor CR, Koster H. The use of MassARRAY technology for high throughput genotyping.  Adv Biochem Eng Biotechnol. 2002;77:57-74PubMed
97.
Jurinke C, Oeth P, van den Boom D. MALDI-TOF mass spectrometry: a versatile tool for high-performance DNA analysis.  Mol Biotechnol. 2004;26:147-164PubMedArticle
98.
Chiodini BD, Barlera S, Franzosi MG, Beceiro VL, Introna M, Tognoni G. APO B gene polymorphisms and coronary artery disease: a meta-analysis.  Atherosclerosis. 2003;167:355-366PubMedArticle
99.
González-Conejero R, Corral J, Roldan V.  et al.  A common polymorphism in the annexin V Kozak sequence (-1C>T) increases translation efficiency and plasma levels of annexin V, and decreases the risk of myocardial infarction in young patients.  Blood. 2002;100:2081-2086PubMed
100.
Hines LM, Stampfer MJ, Ma J.  et al.  Genetic variation in alcohol dehydrogenase and the beneficial effect of moderate alcohol consumption on myocardial infarction.  N Engl J Med. 2001;344:549-555PubMedArticle
101.
Stephens M, Scheet P. Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation.  Am J Hum Genet. 2005;76:449-462PubMedArticle
102.
Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data.  Am J Hum Genet. 2001;68:978-989PubMedArticle
103.
Gauderman WJ. Candidate gene association analysis for a quantitative trait, using parent-offspring trios.  Genet Epidemiol. 2003;25:327-338PubMedArticle
104.
Gauderman WJ. Sample size requirements for matched case-control studies of gene-environment interaction.  Stat Med. 2002;21:35-50PubMedArticle
105.
Weng L, Kavaslar N, Ustaszewska A.  et al.  Lack of MEF2A mutations in coronary artery disease.  J Clin Invest. 2005;115:1016-1020PubMed
106.
Liu S, Ma J, Ridker PM, Breslow JL, Stampfer MJ. A prospective study of the association between APOE genotype and the risk of myocardial infarction among apparently healthy men.  Atherosclerosis. 2003;166:323-329PubMedArticle
107.
 Freely associating.  Nat Genet. 1999;22:1-2PubMedArticle
108.
Salanti G, Sanderson S, Higgins JP. Obstacles and opportunities in meta-analysis of genetic association studies.  Genet Med. 2005;7:13-20PubMedArticle
109.
Marchini J, Cardon LR, Phillips MS, Donnelly P. The effects of human population structure on large genetic association studies.  Nat Genet. 2004;36:512-517PubMedArticle
110.
Gabriel SB, Schaffner SF, Nguyen H.  et al.  The structure of haplotype blocks in the human genome.  Science. 2002;296:2225-2229PubMedArticle
Original Contribution
April 11, 2007

Nonvalidation of Reported Genetic Risk Factors for Acute Coronary Syndrome in a Large-Scale Replication Study

Author Affiliations
 

Author Affiliations: Department of Genetics, Howard Hughes Medical Institute (Drs Morgan and Lifton), Robert Wood Johnson Clinical Scholars Program and Department of Internal Medicine (Dr Krumholz), Yale University School of Medicine, New Haven, Conn, and Mid-America Heart Institute and University of Missouri-Kansas City, Mo (Dr Spertus). Dr Morgan is now with the Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St Louis, Mo.

JAMA. 2007;297(14):1551-1561. doi:10.1001/jama.297.14.1551
Context

Context Given the numerous, yet inconsistent, reports of genetic variants being associated with acute coronary syndromes (ACS), there is a need for comprehensive validation of ACS susceptibility genotypes.

Objective To perform an extensive validation of putative genetic risk factors for ACS.

Design, Setting, and Participants Through a systematic literature search of articles published before March 10, 2005, we identified genetic variants previously reported as significant susceptibility factors for atherosclerosis or ACS. Restricting our analysis to white patients to reduce confounding from racial admixture, we identifed 811 patients who presented from March 2001 through June 2003 with ACS at 2 Kansas City, Mo, university-affiliated hospitals. During 2005-2006, we genotyped the 811 patients along with 650 age- and sex-matched controls for 85 variants in 70 genes and attempted to replicate previously reported associations. We further explored possible associations without prior assumption of specific risk models and used the Sign test to search for weak associations.

Main Outcome Measures Compare each prespecified gene variant associated with ACS risk among cases and controls. A surplus of associations would imply that some are associated with ACS.

Results Of 85 variants tested, only 1 putative risk genotype (−455 promoter variant in β-fibrinogen) was nominally statistically significant (P = .03). Only 4 additional genes were positive in model-free analysis. Neither number of associations was more frequent than expected by chance, given the number of comparisons. Finally, only 41 of 84 predefined risk variants were even marginally more frequent in cases than in controls (with 1 tie), representing a 48.8% “win rate” (95% confidence interval, 38.1%-59.5%) for the collective risk genotypes (P = .91, Sign test).

Conclusions Our null results provide no support for the hypothesis that any of the 85 genetic variants tested is a susceptibility factor for ACS. These results emphasize the need for robust replication of putative genetic risk factors before their introduction into clinical care.

Compelling evidence from twin and epidemiological studies suggests a genetic basis for atherosclerotic heart disease and acute coronary syndromes (ACS), including unstable angina, non–ST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI).1,2 To date, numerous candidate genes have been implicated, mainly by case-control studies, as potential cardiovascular risk factors, but few, if any, have been established definitively.35 Factors undermining the validity of previous reports include inappropriately small sample sizes, multiple subgroup comparisons, and publication bias.4

Before use in clinical care, potential genetic risk factors would ideally be replicated en masse in large, well-characterized patient populations.6 To date, no such comprehensive validation of genetic variants potentially associated with ACS or atherosclerosis has been reported.

Accordingly, we first sought to identify genetic associations with ACS by systematically searching the medical literature for variants reported in association with MI, unstable angina, or atherosclerosis. We then attempted to validate these putative genetic risks in a large case-control study.

METHODS
Candidate Genes

We searched PubMed and bibliographies of original and review articles for manuscripts published before March 10, 2005, that reported statistically significant associations between specific genotypes and coronary atherosclerosis or ACS (A list of the articles is available on request from the authors). MEDLINE search terms included: gene, genetic, polymorphism, myocardial infarction, atherosclerosis, coronary heart disease, and coronary artery disease. Reports were included if they contained a claim of a significant positive association, with an investigator-reported P value <.05. A total of 96 polymorphic genetic variants in 75 genes were identified and included (Table 1 and Table 2). Eleven of those were excluded because they had failed the multiplex genotyping assay.

Description of Cases and Controls

Eight hundred eleven white patients of European ancestry with ACS were identified from a consecutive series of patients presenting at 2 Kansas City, Mo, hospitals (Mid-America Heart Institute and Truman Medical Center), from March 2001 through June 2003. Standard definitions were used to diagnose ACS patients with either MI or unstable angina.92,93 Myocardial infarction was defined by a positive troponin blood test in the setting of symptoms and electrocardiogram changes (both ST-segment elevation and non–ST-segment elevation changes) consistent with MI. Unstable angina diagnoses were confirmed, by concurrence of 3 physician chart reviewers, if patients had negative troponin blood tests and any one of the following: new onset angina (<2 months) of at least Canadian Cardiovascular Society Classification class III, prolonged (>20 minutes) rest angina, recent (<2 months) worsening of angina, or angina that occurred within 2 weeks of an MI.93 Of the troponin-negative unstable angina patients, 203 (92.7%) had a cardiac catheterization, a nuclear stress test, or a stress echocardiogram to corroborate their diagnoses.

Each participating inpatient with ACS was interviewed to determine variables, such as smoking, alcohol use, family history (≥1 first-degree relatives with MI or coronary artery disease), and to obtain consent for a blood sample for genetic analysis. In addition, detailed chart abstractions were performed to collect relevant laboratory and clinical data.

A total of 1045 ACS patients (of which 811 white patients were included in the current study) agreed to participate and to provide a blood sample for genetic analysis. Patients self-reported their race/ethnicity by selecting one of the following descriptors that were provided by the investigators: white, white Hispanic, African American, and African American non-Hispanic. Age- and sex-matched controls were recruited from the ambulatory outpatient clinical laboratory of 1 of the centers, Saint Luke's Hospital of Kansas City. These patients were undergoing routine laboratory testing and were asked to complete a medical questionnaire defining cardiac risk factors and medical co-morbidities. Those controls reporting a previous ACS, prior coronary artery bypass graft surgery or prior percutaneous coronary intervention were excluded. To minimize the potential impact of genetic admixture, 650 white controls of mixed European ancestry who reported no history of coronary artery disease were selected from among the 1054 potential controls. Risk factor data were missing for 9 sex-, age-, and race-matched unaffected controls, and 56 additional matched controls were used for ALOX5AP haplotyping.

The research protocol was approved by the institutional review boards of both institutions; all study participants provided written informed consent for clinical and genetic studies.

Genotyping

Genomic DNA was isolated (Gentra PUREGENE, Minneapolis, Minn) from blood samples and subjected to whole genome amplification by multiple-strand displacement (Molecular Staging Inc, New Haven, Conn), using random priming and Phi-29 polymerase.94,95 Genotyping was performed using the Sequenom MALDI-TOF (Matrix Assisted Laser Desorption-Ionization Time-of-Flight) system, using Spectrodesign software for assay design (Sequenom, San Diego, Calif), and assay methods that have previously been described.96,97 Gene variants were excluded from analysis if they could not be genotyped using the Sequenom system due to persistent assay failure, defined as less than 95% scorable genotypes after 4 multiplex reaction design cycles. Eleven assays were ultimately excluded.13,20,42,45,72,88,98100 For the rare MEF2A 21–base pair (bp) deletion, cases and controls were genotyped by polymerase chain reaction to generate amplicons of 152-bp nondeletion or 131-bp deletion followed by electrophoresis on 3% agarose gels. Identified deletions were confirmed by direct DNA sequencing. Due to its rarity, MEF2A was analyzed separately, and thus only the other 84 genes were subjected to the full set of statistical analyses. PHASE Version 2.1 was used to estimate haplotype frequencies for ALOX5AP.101,102

Statistical Analysis

Genotype distributions in cases and controls were examined for significant deviation (P<.05) from Hardy-Weinberg equilibrium. The number of departures was assessed by Monte Carlo simulation and compared with the number expected by chance alone (Resampling Stats Inc, College Park, Md).

In the primary analysis, each genetic variant was prespecified based on published reports, and the frequencies of risk-associated variants were compared in cases and controls by using a 100 000 iteration Monte Carlo extension of the χ2 test (SPSS 13.0 Exact Tests, SPSS Inc, Chicago, Ill). The term statistically significant was reserved for a P value below the Bonferroni-corrected study-wide significance threshold (0.05/84 = 0.0006). Because the Bonferroni correction is conservative when applied to a replication study, the total number of all positive associations at the P<.05 level was also compared with the expected number by chance in 100 000 simulations. A surplus of positive associations over random expectations would imply that some are truly associated with ACS.

Secondarily, we also compared the overall genotype distributions at each locus in cases and controls by Monte Carlo χ2 testing. Power to confirm individual genetic associations was determined using a log-likelihood-based method (Quanto 1.0).103,104

Finally, as a measure to increase power, the observed proportion of prespecified risk variants found to be even marginally more frequent in cases than in controls was assessed by the Sign test. Under the null hypothesis, each of the risk variants is equally likely to be more frequent in cases, or in controls. To estimate the Sign test's power to detect an excess of even weakly positive genetic associations (50 of 84 positive associations confers P = .05 in the Sign test), we simulated the resampling of 650 control and 811 case genotypes across 84 genetic comparisons, finding the minimum detectable odds ratio ensuring a critical probability level of a 63.3% win rate for each 84 risk variants that provides 80% confidence of having at least 50 wins.

RESULTS

The clinical characteristics of the 811 cases and 650 controls are described in Table 3 and the distributions of their genotypes are shown in Table 2. The population of ACS cases included 308 (38%) STEMI, 284 (35%) NSTEMI, and 219 (27%) unstable angina patients. Cases and controls had similar age, sex, and body mass index distributions. A family history of coronary artery disease or MI among first-degree relatives was 2.7-fold higher in male cases than in male controls and 2.0-fold higher in female cases than in female controls. Male and female cases were significantly more likely to be current smokers and to have type 2 diabetes mellitus but less likely to consume at least 1 alcoholic drink per month. Frequencies of hypercholesterolemia and hypertension were higher in female cases than in controls; no significant differences were observed in males. Previous revascularization had been performed in 35.6% of incident ACS cases and in none of the controls.

A total of 85 variants in 70 genes were genotyped in cases and controls.The overall genotype call rate for these variants was 98.5% (range, 95.0%-99.8%). Two percent of all samples were genotyped in duplicate for each marker in a blinded fashion as a measure of genotype reproducibility. Among the 2511 repeated genotypes, 5 were discordant, demonstrating a reproducibility of 99.8%.

Tests of Hardy-Weinberg equilibrium revealed that 1 variant violated it in both cases and controls, at the P<.05 level; 7 violated it in cases only; and 4 violated it in controls only (Table 1 and Table 2). This finding is not more than expected by chance (4 violations expected by chance in each group; see the Methods section) and therefore none was excluded from further analysis at this stage.

With respect to power parameters, the mean effective frequency (or 1-frequency, if q >0.5) in controls of the putative risk variants studied was 0.20, and 58 (68.2%) were common, (≥0.1), 25 (29.4%) were uncommon (<0.1; >0.01), and 2 (2.4%) were rare (≤0.01). Our sample had 80% power to confirm, by the Monte Carlo χ2 test, a genotype-specific relative risk of 2.3 for a rare variant (q = 0.01), 1.4 for a relatively uncommon variant (q = 0.1), and 1.25 for a common allele (q = 0.5).

We tested whether each putative risk variant showed a significant difference in frequency between cases and controls (Table 1). An odds ratio greater than 1 indicates that the risk genotype was in higher frequency among cases, and if so, the genotype frequency difference was reported as a positive decimal number. Only 1 genetic variant was significant at the P<.05 level, which is the number most likely by chance alone. The −455 variant, which lies upstream of the transcription initiation site in the β-fibrinogen gene, replicated the originally reported association, with the GG genotype being more frequent in cases than controls (frequency, 66% in cases vs 61% in controls; odds ratio, 1.27; P = .03). In addition, we found the MEF2A 21-bp deletion in 1 case and 1 control, confirming that this is a rare variant in the population.105

Several supplementary analyses were performed. When the genotypes of cases and controls were analyzed by extension of 2 × 3 χ2 tests to 100 000 simulations, 4 loci, RECQL2, THBS2, LIPC, and p22-PHOX, were marginally significant (Table 2). In each case, the specific genetic risk model providing significance was different from that reported in the literature; hence, these cannot be considered formal replications and the total number of positive associations is not in excess of random expectations.

Finally, we found that only 41 of 84 predefined risk variants were even marginally more frequent in cases than in controls (excluding 1 tie, the rare MEF2A deletion), representing a 48.8% win rate (95% confidence interval, 38.1%-59.5%) for the collective-risk genotypes. This observed proportion of wins is not different from the expected proportion (50%) under the null hypothesis (P = .91). Table 1 shows that the absolute differences in risk genotype frequencies between cases and controls (negative signs meaning that the putative risk genotype was more frequent in controls than in cases) were small, with a median difference of −0.0003, and maximum of 0.056 (β fibrinogen).

COMMENT

We were unable to confirm as risk factors for ACS 85 genetic variants because none was unequivocally validated in this large case-control study of 1461 participants. In the primary analysis, only the −455 promoter variant in β-fibrinogen) was nominally statistically significant (P = .03). Among the 4 variants in the secondary analysis that met nominal statistical thresholds, there was an excess of a different variant than was previously reported among cases in the original study, which does not support replication. We therefore conclude that our findings, in this large sample of well-characterized ACS patients and controls, cannot support that this panel of gene variants contains bona fide ACS risk factors.

Our findings come at a critical juncture in complex disease genetics. Some cardiovascular gene variants (eg, ACE, AGT, AGTR1, ITGB3, F2, F5, MTHFR) included in our study can already be ordered clinically, for indications that explicitly include possible ACS risk. However, our findings suggest that such clinical genetic testing is premature and underscore the importance of robust replication studies of reported associations prior to their application to clinical care.

These nonreplications include variants in several high-profile studies. For example, haplotypes A and B of 5-lipoxygenase activating protein (ALOX5AP) were reported in 1 study to be associated with MI in the general populations of Iceland, and the United Kingdom, respectively.17 We found neither haplotype was associated with ACS, in spite of our observed haplotype frequencies in cases and controls closely approximating those found in the total United Kingdom data set (cases and controls) previously (haplotype A, 0.165 vs 0.160, respectively; haplotype B, 0.062 vs 0.058).

Although our study raises significant doubts about the collective panel of putative genetic risk factors, it does not invalidate any particular previous study. Possible explanations of our negative results could include: (1) false-negative results in our study; (2) false-positive associations in previous studies; and (3) varied effects of risk variants in different genetic backgrounds.

False-negative results as a general explanation for our study's null findings are unlikely given that our sample size is substantially larger than all but a few reported prior studies and was powered to detect modest relative risks. Based on a random sample (n = 30) of articles included in this study (1 per gene variant), we estimated that the mean odds ratio reported in positive studies was 2.3 (range, 1.25-5.0), indicating that we had well in excess of 80% power to replicate most reports. However, isolated positive reports may overestimate genetic risks.5,6 Recently, a meta-analysis of 14 genes included in our study reported odds ratios ranging from 1.10 to 1.73 for risk of MI.3 It is possible that minute odds ratios are to be expected in complex disease genetics and that neither our study nor most previous studies were sufficiently powered. Accordingly, we augmented our power, by use of the Sign test, to detect a surplus of as few as 16 weakly positive genetic risk factors among the entire set that we genotyped (84 −16 = 50, the number required for a significant Sign test), corresponding to a mean odds ratio of 1.05 or higher given our sample size and the average risk genotype frequency.

Absence of genetic effect only in our cohort is also unlikely. Cases showed a 2-fold higher family history of ACS, consistent with a genetic effect contributing to phenotypes in this cohort. In addition, homozygosity coding for an arginine residue at position 158 of apolipoprotein E (E4 variant), considered 1 of the least controversial of the putative ACS susceptibility factors despite some inconsistency in certain cohorts,106 was significantly associated (P = .04) among cases with hyperlipidemia (4.1%) vs controls without hyperlipidemia (1.6%).

False-positive results in previous studies are another potential explanation for the discrepancy between our findings and those of others. This issue has previously been recognized as a serious problem with association studies, particularly when sample sizes are underpowered.107 It is difficult to identify true vs false positives by analysis of the literature alone.108 Unrecognized stratification between cases and controls can create spurious associations,109 and the absence of negative genomic controls in nearly all prior studies to exclude this possibility leaves this an open question. Also difficult to assess is the extent to which publication bias and multiple hypothesis testing have had an effect.

It could be argued that our research participants are distinct from those reported previously and that our results may not bear on the validity of positive associations reported in different populations and clinical subgroups (eg, analyses substratified by age, sex, or a clinical variable, such as hypertension, hyperlipidemia, or smoking status). Given that the vast majority of common variants in the human genome date to our shared ancestry in Africa,110 it is not likely that there are different common functional variants in linkage disequilibrium with risk variants in our population vs others. Less common mutations of more recent ancestral origin could conceivably be correlated with certain genetic variants in one population but not another. The extent to which linkage disequilibrium patterns might explain our findings is unknown, but our study population is quite typical of the mixed European background that is prevalent in the United States.

Another possibility is that the effect of risk variants is different in different genetic backgrounds; if true, the lack of generalizability of results will severely limit their application to the clinical arena. The fact that we failed to replicate positive associations in a consecutive series of study participants that are broadly representative of the disease encountered in clinical practice places limitations on the potential applicability of prior findings and supports our premise that it is premature to extrapolate these earlier findings to routine clinical care.

The failure of the candidate gene approach to identify variants conferring susceptibility to ACS risk prompts consideration of other approaches. One promising approach is to screen the entire genome in an unbiased way in a large sample for variants that are significantly associated with disease risk. Coupled with the understanding of underlying patterns of linkage disequilibrium in the human genome7 and the ability to inexpensively obtain genotypes across the genome, the field is moving rapidly toward a comprehensive genome-wide approach. Challenges of this approach include the unknown number of variants that impart effect, the magnitude of the effect imparted by each, and the extent to which common variants as opposed to rare independent mutations account for disease risk.

Regardless of the approach taken, it is clear that multiple large, well-matched cohorts of cases and controls will be required to achieve valid progress in the genetic analysis of ACS and other complex human diseases. Our null findings indicate the need for caution in the interpretation of genetic associations in different clinical populations and the need for extensive validation of genetic risk factors.

Back to top
Article Information

Corresponding Author: Thomas M. Morgan, MD, Washington University School of Medicine, McDonnell Pediatric Research Bldg, 3103, 660 Euclid Ave, St Louis, MO 63110, (email: morgan_t@kids.wustl.edu) or Richard P. Lifton, MD, PhD, Yale University School of Medicine, 295 Congress Ave, New Haven, CT 06510 (richard.lifton@yale.edu).

Author Contributions: Dr Morgan had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Morgan, Lifton, Krumholz, Spertus.

Acquisition of data: Morgan, Lifton, Krumholz, Spertus.

Analysis and interpretation of data: Morgan, Lifton, Krumholz, Spertus.

Drafting of the manuscript: Morgan, Lifton, Krumholz, Spertus.

Critical revision of the manuscript for important intellectual content: Morgan, Lifton, Krumholz.

Statistical analysis: Morgan, Lifton.

Obtained funding: Morgan, Lifton, Spertus.

Administrative, technical, or material support: Lifton, Spertus.

Study supervision: Lifton, Krumholz, Spertus.

Financial Disclosures: Dr Spertus reports that he serves on the advisory boards of the American College of Cardiology, American Heart Association, Amgen United Healthcare, Blue Cross/Blue Shield; has received gants from the National Institutes of Health (NIH), Amgen, CV Therapeutics, Flowcardia, and Roache Diagnostics (in-kind biomarker reagent supplies for an NIH grant); has ownership interests in the Seattle Angina Questionnaire, the Kansas City Cardiomyopathy Questionnaire, the Peripheral Artery Questionnaire, and Health Outcomes Sciences; and has consulted within the past 5 years for CV Therapeutics, Amgen, Worldheart, and Ostuka Parmaceuticals. Dr Krumholz reports that he has research contracts with the Colorado Foundation for Medical Care and the American College of Cardiology, serves on the advisory boards for Amgen, Alere, and United Healthcare, is a subject-matter expert for VHA Inc. Drs Morgan and Lifton report no conflicts of interest.

Funding/Support: This project was funded by grants from the Saint Luke's Hospital Foundation, Kansas City, Mo, and by grant R-01 HS11282-01 from the Agency for Healthcare Research and Quality. Dr Morgan's research in Dr Lifton's laboratory at Yale University was supported by Howard Hughes Medical Institute and by grant NHLBI K23 HI77272, a mentored patient-oriented research grant from the National Heart, Lung, and Blood Institute.

Role of the Sponsor: None of the funding organizations had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Acknowledgment: We thank Donna Buchanan, PhD, Mid-America Heart Institute, Kansas City, Mo, for editorial assistance with the manuscript as part of her duties and received no additional compensation.

This article was corrected for typographical errors on 9/6/2007.

REFERENCES
1.
Marenberg ME, Risch N, Berkman LF, Floderus B, de Faire U. Genetic susceptibility to death from coronary heart disease in a study of twins.  N Engl J Med. 1994;330:1041-1046PubMedArticle
2.
Scheuner MT. Clinical application of genetic risk assessment strategies for coronary artery disease: genotypes, phenotypes, and family history.  Prim Care. 2004;31:711-737, xi-xiiPubMedArticle
3.
Casas JPCJ, Miller GJ, Hingorani AD, Humphries SE. Investigating the genetic determinants of cardiovascular disease using candidate genes and meta-analysis of association studies.  Ann Hum Genet. 2006;70:145-169PubMedArticle
4.
Morgan TM, Coffey CS, Krumholz HM. Overestimation of genetic risks owing to small sample sizes in cardiovascular studies.  Clin Genet. 2003;6 4:7-17PubMedArticle
5.
Yamada Y. Identification of genetic factors and development of genetic risk diagnosis systems for cardiovascular diseases and stroke.  Circ J. 2006;70:1240-1248PubMedArticle
6.
Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG. Replication validity of genetic association studies.  Nat Genet. 2001;29:306-309PubMedArticle
7.
The International HapMap Consortium.  The International HapMap Project.  Nature. 2003;426:789-796PubMedArticle
8.
Lutucuta S, Ballantyne CM, Elghannam H, Gotto AM Jr, Marian AJ. Novel polymorphisms in promoter region of ATP binding cassette transporter gene and plasma lipids, severity, progression, and regression of coronary atherosclerosis and response to therapy.  Circ Res. 2001;88:969-973PubMedArticle
9.
Zwarts KY, Clee SM, Zwinderman AH.  et al.  ABCA1 regulatory variants influence coronary artery disease independent of effects on plasma lipid levels.  Clin Genet. 2002;61:115-125PubMedArticle
10.
Clee SM, Zwinderman AH, Engert JC.  et al.  Common genetic variation in ABCA1 is associated with altered lipoprotein levels and a modified risk for coronary artery disease.  Circulation. 2001;103:1198-1205PubMedArticle
11.
Tregouet DA, Ricard S, Nicaud V.  et al.  In-depth haplotype analysis of ABCA1 gene polymorphisms in relation to plasma ApoA1 levels and myocardial infarction.  Arterioscler Thromb Vasc Biol. 2004;24:775-781PubMedArticle
12.
Tobin MD, Braund PS, Burton PR.  et al.  Genotypes and haplotypes predisposing to myocardial infarction: a multilocus case-control study.  Eur Heart J. 2004;25:459-467PubMedArticle
13.
Zee RY, Cook NR, Reynolds R, Cheng S, Ridker PM. Haplotype analysis of the beta2 adrenergic receptor gene and risk of myocardial infarction in humans.  Genetics. 2005;169:1583-1587PubMedArticle
14.
Higashi K, Ishikawa T, Ito T, Yonemura A, Shige H, Nakamura H. Association of a genetic variation in the beta 3-adrenergic receptor gene with coronary heart disease among Japanese.  Biochem Biophys Res Commun. 1997;232:728-730PubMedArticle
15.
Sethi AA, Nordestgaard BG, Tybjaerg-Hansen A. Angiotensinogen gene polymorphism, plasma angiotensinogen, and risk of hypertension and ischemic heart disease: a meta-analysis.  Arterioscler Thromb Vasc Biol. 2003;23:1269-1275PubMedArticle
16.
Fatini C, Abbate R, Pepe G.  et al.  Searching for a better assessment of the individual coronary risk profile: the role of angiotensin-converting enzyme, angiotensin II type 1 receptor and angiotensinogen gene polymorphisms.  Eur Heart J. 2000;21:633-638PubMedArticle
17.
Helgadottir A, Manolescu A, Thorleifsson G.  et al.  The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke.  Nat Genet. 2004;36:233-239PubMedArticle
18.
Wang XL, Liu SX, McCredie RM, Wilcken DE. Polymorphisms at the 5′-end of the apolipoprotein AI gene and severity of coronary artery disease.  J Clin Invest. 1996;98:372-377PubMedArticle
19.
Reguero JR, Cubero GI, Batalla A.  et al.  Apolipoprotein A1 gene polymorphisms and risk of early coronary disease.  Cardiology. 1998;90:231-235PubMedArticle
20.
Wilson PW, Schaefer EJ, Larson MG, Ordovas JM. Apolipoprotein E alleles and risk of coronary disease: a meta-analysis.  Arterioscler Thromb Vasc Biol. 1996;16:1250-1255PubMedArticle
21.
Lambert JC, Brousseau T, Defosse V.  et al.  Independent association of an APOE gene promoter polymorphism with increased risk of myocardial infarction and decreased APOE plasma concentrations-the ECTIM study.  Hum Mol Genet. 2000;9:57-61PubMedArticle
22.
Aoki S, Mukae S, Itoh S.  et al.  The genetic factor in acute myocardial infarction with hypertension.  Jpn Circ J. 2001;65:621-626PubMedArticle
23.
Zee RY, Cook NR, Cheng S.  et al.  Threonine for alanine substitution in the eotaxin (CCL11) gene and the risk of incident myocardial infarction.  Atherosclerosis. 2004;175:91-94PubMedArticle
24.
Ortlepp JR, Vesper K, Mevissen V.  et al.  Chemokine receptor (CCR2) genotype is associated with myocardial infarction and heart failure in patients under 65 years of age.  J Mol Med. 2003;81:363-367PubMedArticle
25.
González P, Alvarez R, Batalla A.  et al.  Genetic variation at the chemokine receptors CCR5/CCR2 in myocardial infarction.  Genes Immun. 2001;2:191-195PubMedArticle
26.
Hubacek JA, Rothe G, Pit'ha J.  et al.  C(−260)→T polymorphism in the promoter of the CD14 monocyte receptor gene as a risk factor for myocardial infarction.  Circulation. 1999;99:3218-3220PubMedArticle
27.
Kuivenhoven JA, Jukema JW, Zwinderman AH.  et al. the Regression Growth Evaluation Statin Study Group.  The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis.  N Engl J Med. 1998;338:86-93PubMedArticle
28.
Klerkx AH, Tanck MW, Kastelein JJ.  et al.  Haplotype analysis of the CETP gene: not TaqIB, but the closely linked −629C→A polymorphism and a novel promoter variant are independently associated with CETP concentration.  Hum Mol Genet. 2003;12:111-123PubMedArticle
29.
Eriksson AL, Skrtic S, Niklason A.  et al.  Association between the low activity genotype of catechol-O-methyltransferase and myocardial infarction in a hypertensive population.  Eur Heart J. 2004;25:386-391PubMedArticle
30.
Niessner A, Marculescu R, Haschemi A.  et al.  Opposite effects of CX3CR1 receptor polymorphisms V249I and T280M on the development of acute coronary syndrome: a possible implication of fractalkine in inflammatory activation.  Thromb Haemost. 2005;93:949-954PubMed
31.
McDermott DH, Halcox JP, Schenke WH.  et al.  Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis.  Circ Res. 2001;89:401-407PubMedArticle
32.
Patel S, Steeds R, Channer K, Samani NJ. Analysis of promoter region polymorphism in the aldosterone synthase gene (CYP11B2) as a risk factor for myocardial infarction.  Am J Hypertens. 2000;13:134-139PubMedArticle
33.
Hautanen A, Toivanen P, Manttari M.  et al.  Joint effects of an aldosterone synthase (CYP11B2) gene polymorphism and classic risk factors on risk of myocardial infarction.  Circulation. 1999;100:2213-2218PubMedArticle
34.
Yasar U, Bennet AM, Eliasson E.  et al.  Allelic variants of cytochromes P450 2C modify the risk for acute myocardial infarction.  Pharmacogenetics. 2003;13:715-720PubMedArticle
35.
Funk M, Endler G, Freitag R.  et al.  CYP2C9*2 and CYP2C9*3 alleles confer a lower risk for myocardial infarction.  Clin Chem. 2004;50:2395-2398PubMedArticle
36.
Endler G, Mannhalter C, Sunder-Plassmann H.  et al.  The K121Q polymorphism in the plasma cell membrane glycoprotein 1 gene predisposes to early myocardial infarction.  J Mol Med. 2002;80:791-795PubMedArticle
37.
Schuit SC, Oei HH, Witteman JC.  et al.  Estrogen receptor alpha gene polymorphisms and risk of myocardial infarction.  JAMA. 2004;291:2969-2977PubMedArticle
38.
Shearman AM, Cupples LA, Demissie S.  et al.  Association between estrogen receptor alpha gene variation and cardiovascular disease.  JAMA. 2003;290:2263-2270PubMedArticle
39.
Endler G, Mannhalter C, Sunder-Plassmann H.  et al.  Homozygosity for the C→T polymorphism at nucleotide 46 in the 5′ untranslated region of the factor XII gene protects from development of acute coronary syndrome.  Br J Haematol. 2001;115:1007-1009PubMedArticle
40.
Endler G, Mannhalter C. Polymorphisms in coagulation factor genes and their impact on arterial and venous thrombosis.  Clin Chim Acta. 2003;330:31-55PubMedArticle
41.
Rosendaal FR, Siscovick DS, Schwartz SM, Psaty BM, Raghunathan TE, Vos HL. A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women.  Blood. 1997;90:1747-1750PubMed
42.
Girelli D, Russo C, Ferraresi P.  et al.  Polymorphisms in the factor VII gene and the risk of myocardial infarction in patients with coronary artery disease.  N Engl J Med. 2000;343:774-780PubMedArticle
43.
Boekholdt SM, Bijsterveld NR, Moons AH, Levi M, Buller HR, Peters RJ. Genetic variation in coagulation and fibrinolytic proteins and their relation with acute myocardial infarction: a systematic review.  Circulation. 2001;104:3063-3068PubMedArticle
44.
Yamada Y, Izawa H, Ichihara S.  et al.  Prediction of the risk of myocardial infarction from polymorphisms in candidate genes.  N Engl J Med. 2002;347:1916-1923PubMedArticle
45.
Kenny D, Muckian C, Fitzgerald DJ, Cannon CP, Shields DC. Platelet glycoprotein Ib alpha receptor polymorphisms and recurrent ischaemic events in acute coronary syndrome patients.  J Thromb Thrombolysis. 2002;13:13-19PubMedArticle
46.
Douglas H, Michaelides K, Gorog DA.  et al.  Platelet membrane glycoprotein Ibalpha gene −5T/C Kozak sequence polymorphism as an independent risk factor for the occurrence of coronary thrombosis.  Heart. 2002;87:70-74PubMedArticle
47.
Lin RC, Wang XL, Morris BJ. Association of coronary artery disease with glucocorticoid receptor N363S variant.  Hypertension. 2003;41:404-407PubMedArticle
48.
Hetet G, Elbaz A, Gariepy J.  et al.  Association studies between haemochromatosis gene mutations and the risk of cardiovascular diseases.  Eur J Clin Invest. 2001;31:382-388PubMedArticle
49.
Yamada S, Akita H, Kanazawa K.  et al.  T102C polymorphism of the serotonin (5-HT) 2A receptor gene in patients with non-fatal acute myocardial infarction.  Atherosclerosis. 2000;150:143-148PubMedArticle
50.
Jiang H, Klein RM, Niederacher D.  et al.  C/T polymorphism of the intercellular adhesion molecule-1 gene (exon 6, codon 469): a risk factor for coronary heart disease and myocardial infarction.  Int J Cardiol. 2002;84:171-177PubMedArticle
51.
Momiyama Y, Hirano R, Taniguchi H, Nakamura H, Ohsuzu F. Effects of interleukin-1 gene polymorphisms on the development of coronary artery disease associated with Chlamydia pneumoniae infection.  J Am Coll Cardiol. 2001;38:712-717PubMedArticle
52.
Georges JL, Loukaci V, Poirier O.  et al. Etude Cas-Temoin de l'Infarctus du Myocarde.  Interleukin-6 gene polymorphisms and susceptibility to myocardial infarction: the ECTIM study.  J Mol Med. 2001;79:300-305PubMedArticle
53.
Jenny NS, Tracy RP, Ogg MS.  et al.  In the elderly, interleukin-6 plasma levels and the −174G>C polymorphism are associated with the development of cardiovascular disease.  Arterioscler Thromb Vasc Biol. 2002;22:2066-2071PubMedArticle
54.
Baroni MG, D'Andrea MP, Montali A.  et al.  A common mutation of the insulin receptor substrate-1 gene is a risk factor for coronary artery disease.  Arterioscler Thromb Vasc Biol. 1999;19:2975-2980PubMedArticle
55.
Santoso S, Kunicki TJ, Kroll H, Haberbosch W, Gardemann A. Association of the platelet glycoprotein Ia C807T gene polymorphism with nonfatal myocardial infarction in younger patients.  Blood. 1999;93:2449-2453PubMed
56.
Samara WM, Gurbel PA. The role of platelet receptors and adhesion molecules in coronary artery disease.  Coron Artery Dis. 2003;14:65-79PubMedArticle
57.
Zambon A, Deeb SS, Pauletto P, Crepaldi G, Brunzell JD. Hepatic lipase: a marker for cardiovascular disease risk and response to therapy.  Curr Opin Lipidol. 2003;14:179-189PubMedArticle
58.
Ji J, Herbison CE, Mamotte CD, Burke V, Taylor RR, van Bockxmeer FM. Hepatic lipase gene −514 C/T polymorphism and premature coronary heart disease.  J Cardiovasc Risk. 2002;9:105-113PubMedArticle
59.
Hokanson JE. Functional variants in the lipoprotein lipase gene and risk cardiovascular disease.  Curr Opin Lipidol. 1999;10:393-399PubMedArticle
60.
Schulz S, Schagdarsurengin U, Greiser P.  et al.  The LDL receptor-related protein (LRP1/A2MR) and coronary atherosclerosis–novel genomic variants and functional consequences.  Hum Mutat. 2002;20:404PubMedArticle
61.
PROCARDIS Consortium.  A trio family study showing association of the lymphotoxin-alpha N26 (804A) allele with coronary artery disease.  Eur J Hum Genet. 2004;12:770-774PubMedArticle
62.
Ozaki K, Ohnishi Y, Iida A.  et al.  Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction.  Nat Genet. 2002;32:650-654PubMedArticle
63.
Herrmann SM, Whatling C, Brand E.  et al.  Polymorphisms of the human matrix gla protein (MGP) gene, vascular calcification, and myocardial infarction.  Arterioscler Thromb Vasc Biol. 2000;20:2386-2393PubMedArticle
64.
Humphries SE, Martin S, Cooper J, Miller G. Interaction between smoking and the stromelysin-1 (MMP3) gene 5A/6A promoter polymorphism and risk of coronary heart disease in healthy men.  Ann Hum Genet. 2002;66:343-352PubMedArticle
65.
Lamblin N, Bauters C, Hermant X, Lablanche JM, Helbecque N, Amouyel P. Polymorphisms in the promoter regions of MMP-2, MMP-3, MMP-9 and MMP-12 genes as determinants of aneurysmal coronary artery disease.  J Am Coll Cardiol. 2002;40:43-48PubMedArticle
66.
Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG. MTHFR 677C→T polymorphism and risk of coronary heart disease: a meta-analysis.  JAMA. 2002;288:2023-2031PubMedArticle
67.
Ledmyr H, McMahon AD, Ehrenborg E.  et al.  The microsomal triglyceride transfer protein gene-493T variant lowers cholesterol but increases the risk of coronary heart disease.  Circulation. 2004;109:2279-2284PubMedArticle
68.
Juo SH, Han Z, Smith JD, Colangelo L, Liu K. Common polymorphism in promoter of microsomal triglyceride transfer protein gene influences cholesterol, ApoB, and triglyceride levels in young African American men: results from the coronary artery risk development in young adults (CARDIA) study.  Arterioscler Thromb Vasc Biol. 2000;20:1316-1322PubMedArticle
69.
Hyndman ME, Bridge PJ, Warnica JW, Fick G, Parsons HG. Effect of heterozygosity for the methionine synthase 2756 A→G mutation on the risk for recurrent cardiovascular events.  Am J Cardiol. 2000;86:1144-1146, A1149PubMedArticle
70.
Gruchala M, Ciecwierz D, Wasag B.  et al.  Association of the ScaI atrial natriuretic peptide gene polymorphism with nonfatal myocardial infarction and extent of coronary artery disease.  Am Heart J. 2003;145:125-131PubMedArticle
71.
Tatsuguchi M, Furutani M, Hinagata J.  et al.  Oxidized LDL receptor gene (OLR1) is associated with the risk of myocardial infarction.  Biochem Biophys Res Commun. 2003;303:247-250PubMedArticle
72.
Gardemann A, Mages P, Katz N, Tillmanns H, Haberbosch W. The p22 phox A640G gene polymorphism but not the C242T gene variation is associated with coronary heart disease in younger individuals.  Atherosclerosis. 1999;145:315-323PubMedArticle
73.
Inoue N, Kawashima S, Kanazawa K, Yamada S, Akita H, Yokoyama M. Polymorphism of the NADH/NADPH oxidase p22-phox gene in patients with coronary artery disease.  Circulation. 1998;97:135-137PubMedArticle
74.
Wenzel K, Baumann G, Felix SB. The homozygous combination of Leu125Val and Ser563Asn polymorphisms in the PECAM1 (CD31) gene is associated with early severe coronary heart disease.  Hum Mutat. 1999;14:545PubMedArticle
75.
Andreotti F, Porto I, Crea F, Maseri A. Inflammatory gene polymorphisms and ischaemic heart disease: review of population association studies.  Heart. 2002;87:107-112PubMedArticle
76.
Durrington PN, Mackness B, Mackness MI. Paraoxonase and atherosclerosis.  Arterioscler Thromb Vasc Biol. 2001;21:473-480PubMedArticle
77.
Sanghera DK, Aston CE, Saha N, Kamboh MI. DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease.  Am J Hum Genet. 1998;62:36-44PubMedArticle
78.
Ridker PM, Cook NR, Cheng S.  et al.  Alanine for proline substitution in the peroxisome proliferator-activated receptor gamma-2 (PPARG2) gene and the risk of incident myocardial infarction.  Arterioscler Thromb Vasc Biol. 2003;23:859-863PubMedArticle
79.
Cipollone F, Toniato E, Martinotti S.  et al.  A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke.  JAMA. 2004;291:2221-2228PubMedArticle
80.
Ye L, Miki T, Nakura J.  et al.  Association of a polymorphic variant of the Werner helicase gene with myocardial infarction in a Japanese population.  Am J Med Genet. 1997;68:494-498PubMedArticle
81.
Herrmann SM, Ricard S, Nicaud V.  et al.  The P-selectin gene is highly polymorphic: reduced frequency of the Pro715 allele carriers in patients with myocardial infarction.  Hum Mol Genet. 1998;7:1277-1284PubMedArticle
82.
Moatti D, Seknadji P, Galand C.  et al.  Polymorphisms of the tissue factor pathway inhibitor (TFPI) gene in patients with acute coronary syndromes and in healthy subjects: impact of the V264M substitution on plasma levels of TFPI.  Arterioscler Thromb Vasc Biol. 1999;19:862-869PubMedArticle
83.
Chao TH, Li YH, Chen JH.  et al.  Relation of thrombomodulin gene polymorphisms to acute myocardial infarction in patients <or =50 years of age.  Am J Cardiol. 2004;93:204-207PubMedArticle
84.
Doggen CJ, Kunz G, Rosendaal FR.  et al.  A mutation in the thrombomodulin gene, 127G to A coding for Ala25Thr, and the risk of myocardial infarction in men.  Thromb Haemost. 1998;80:743-748PubMed
85.
Wu KK, Aleksic N, Ahn C, Boerwinkle E, Folsom AR, Juneja H. Thrombomodulin Ala455Val polymorphism and risk of coronary heart disease.  Circulation. 2001;103:1386-1389PubMedArticle
86.
Topol EJ, McCarthy J, Gabriel S.  et al.  Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction.  Circulation. 2001;104:2641-2644PubMedArticle
87.
Boekholdt SM, Trip MD, Peters RJ.  et al.  Thrombospondin-2 polymorphism is associated with a reduced risk of premature myocardial infarction.  Arterioscler Thromb Vasc Biol. 2002;22:e24-e27PubMedArticle
88.
Webb KE, Martin JF, Hamsten A.  et al.  Polymorphisms in the thrombopoietin gene are associated with risk of myocardial infarction at a young age.  Atherosclerosis. 2001;154:703-711PubMedArticle
89.
Kolek MJ, Carlquist JF, Muhlestein JB.  et al.  Toll-like receptor 4 gene Asp299Gly polymorphism is associated with reductions in vascular inflammation, angiographic coronary artery disease, and clinical diabetes.  Am Heart J. 2004;148:1034-1040PubMedArticle
90.
Padovani JC, Pazin-Filho A, Simoes MV, Marin-Neto JA, Zago MA, Franco RF. Gene polymorphisms in the TNF locus and the risk of myocardial infarction.  Thromb Res. 2000;100:263-269PubMedArticle
91.
Poirier O, Nicaud V, Gariepy J.  et al.  Polymorphism R92Q of the tumour necrosis factor receptor 1 gene is associated with myocardial infarction and carotid intima-media thickness–the ECTIM, AXA, EVA and GENIC Studies.  Eur J Hum Genet. 2004;12:213-219PubMedArticle
92.
Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined—a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction.  J Am Coll Cardiol. 2000;36:959-969PubMedArticle
93.
Braunwald E. Unstable angina: a classification.  Circulation. 1989;80:410-414PubMedArticle
94.
Yan J, Feng J, Hosono S, Sommer SS. Assessment of multiple displacement amplification in molecular epidemiology.  Biotechniques. 2004;37:136-138, 140-133PubMed
95.
Dean FB, Hosono S, Fang L.  et al.  Comprehensive human genome amplification using multiple displacement amplification.  Proc Natl Acad Sci U S A. 2002;99:5261-5266PubMedArticle
96.
Jurinke C, van den Boom D, Cantor CR, Koster H. The use of MassARRAY technology for high throughput genotyping.  Adv Biochem Eng Biotechnol. 2002;77:57-74PubMed
97.
Jurinke C, Oeth P, van den Boom D. MALDI-TOF mass spectrometry: a versatile tool for high-performance DNA analysis.  Mol Biotechnol. 2004;26:147-164PubMedArticle
98.
Chiodini BD, Barlera S, Franzosi MG, Beceiro VL, Introna M, Tognoni G. APO B gene polymorphisms and coronary artery disease: a meta-analysis.  Atherosclerosis. 2003;167:355-366PubMedArticle
99.
González-Conejero R, Corral J, Roldan V.  et al.  A common polymorphism in the annexin V Kozak sequence (-1C>T) increases translation efficiency and plasma levels of annexin V, and decreases the risk of myocardial infarction in young patients.  Blood. 2002;100:2081-2086PubMed
100.
Hines LM, Stampfer MJ, Ma J.  et al.  Genetic variation in alcohol dehydrogenase and the beneficial effect of moderate alcohol consumption on myocardial infarction.  N Engl J Med. 2001;344:549-555PubMedArticle
101.
Stephens M, Scheet P. Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation.  Am J Hum Genet. 2005;76:449-462PubMedArticle
102.
Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data.  Am J Hum Genet. 2001;68:978-989PubMedArticle
103.
Gauderman WJ. Candidate gene association analysis for a quantitative trait, using parent-offspring trios.  Genet Epidemiol. 2003;25:327-338PubMedArticle
104.
Gauderman WJ. Sample size requirements for matched case-control studies of gene-environment interaction.  Stat Med. 2002;21:35-50PubMedArticle
105.
Weng L, Kavaslar N, Ustaszewska A.  et al.  Lack of MEF2A mutations in coronary artery disease.  J Clin Invest. 2005;115:1016-1020PubMed
106.
Liu S, Ma J, Ridker PM, Breslow JL, Stampfer MJ. A prospective study of the association between APOE genotype and the risk of myocardial infarction among apparently healthy men.  Atherosclerosis. 2003;166:323-329PubMedArticle
107.
 Freely associating.  Nat Genet. 1999;22:1-2PubMedArticle
108.
Salanti G, Sanderson S, Higgins JP. Obstacles and opportunities in meta-analysis of genetic association studies.  Genet Med. 2005;7:13-20PubMedArticle
109.
Marchini J, Cardon LR, Phillips MS, Donnelly P. The effects of human population structure on large genetic association studies.  Nat Genet. 2004;36:512-517PubMedArticle
110.
Gabriel SB, Schaffner SF, Nguyen H.  et al.  The structure of haplotype blocks in the human genome.  Science. 2002;296:2225-2229PubMedArticle
×