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Genetic Marker (s) Of MI – One, One Hundred,
or One Thousand?!
Provided by:
M. Bidya Sagar, Ph.D.
Structural Biology and Drug Discovery Laboratory
Center for Vulnerable Plaque Research
Texas Heart Institute
Editorial Slides
VP Watch – December 26, 2002 - Volume 2, Issue 51
 Rupture prone vulnerable plaques are
the predominant underlying process in the
pathogenesis of acute coronary syndromes.
 Although the morphology of these vulnerable
plaques has been studied extensively, the
underlying genetic markers of these plaques
and patients in whom vulnerable plaque
develop, suffer a fatal cardiovascular event, are
largely unknown.
• Genomic and Proteomic research may shed light
on the way to discover these markers of
plaque/patient vulnerability.
• Human Genome studies are underway to identify:
– differential expression of up- and down-regulated genes
in plaque vs normal arterial walls, and comparison of
the mRNA expression at different stages of plaque
development.
– single nucleotide polymorphism (SNP) among
cardiovascular disease patients vs. normal subjects.
– loci on chromosomes through linkage studies
Several studies compared the gene
expression of :
• activated human umbilical vein endothelial
cells
• vascular smooth muscle cells
• cholesterol-loaded macrophages with
that of nonactivated cells.1-3
1-Gene Expression Studies in Plaque
 Studies in cell lines revealed differential
regulation of genes involved in leukocyte
trafficking, cell-cycle control, and
apoptosis.
 Differences in gene expression have
been observed among fatty streaks and
advanced lesions 4
and intima and media
of human atherosclerotic plaques. 5
1- Gene Expression Studies in Plaque
 Tyson et al studied heterogeneity of gene
expression in human atheroma using cDNA
analysis. 6
 Faber et al have suggested perilipine, as
well as other genes potentially involved in
rupture of human atherosclerotic plaques.7-8
1- Gene Expression Studies in Plaque
 Genetic-linkage studies 11
and candidate
gene analyses 12-16
have implicated a
locus and several genes related to
predisposition to myocardial infraction.
 A linkage analysis for myocardial
infarction and its related risk factors was
carried out by Broecke et al. 11
2- Genetic Linkage Studies
 They have scanned the whole genome in
513 families to identify chromosomal regions
linked to MI
 They showed the risk of MI maps to a single
region on chromosome 14 with a significant
lod score of 3.9 (pointwise P=0.00015,
genome-wide P<0.05).
2- Genetic Linkage Studies
 Human Genome mapping has led to a
massive search for clinically relevant
genomic information: including (SNPs),
which consist of substitutions of one
nucleotide for another in a DNA sequence.
 Human genomes are 99.9% identical with
only 0.1% of the genome showing
polymorphisms.9-10
3- Gene Polymorphism (SNP) Studies
 About 2-3 million SNPs have been found in
exonic, intronic, regulatory, and intergenic
regions.9-10
 Though almost all genes contain SNPs, only
a minority of SNPs result in amino acid
variation in proteins. 9-10
3- Gene Polymorphism (SNP) Studies
 Myocardial infarction is a complex
multifactorial and polygenic disorder; and
therefore, it may not be possible to find an
specific genetic make-up predicting the
disease.
 Genetic polymorphisms have been associated
with myocardial infarction and angina pectoris. 20
3- Gene Polymorphism (SNP) Studies
 Fu L et al., investigated the association
between gene polymorphism of the
plasminogen activator inhibitor-1 (PAI-1) and
MI in a Chinese population.17
 The 5A/6A polymorphism in the promoter of
the stromelysin gene has been identified as a
novel pathogenetic risk factor for MI. 18
 Polymorphisms of the P-selectin gene and
risk of MI in men and women has been
reported.19
Gene Polymorphism (SNP) Studies
 As reported in VP Watch of
this week, Yamada et al., published in
the New England Journal of Medicine,
discovery of new polymorphisms in
candidate genes that confer susceptibility
to myocardial infarction. 20
Method:
 A fluorescence- or colorimetry-based allele-
specific DNA-primer-probe assay
 To determine Genotypes of 112
polymorphisms of 71 candidate genes in
2819 unrelated Japanese patients with MI
(2003 men and 816 women) and 2242
unrelated Japanese controls (1306 men and
936 women).
Results:
 Screening of the 112 polymorphisms for an
association with MI in 909 subjects.
 19 polymorphisms were selected in men and
18 in women by means of logistic-regression
analysis, after adjustment for age, BMI, the
prevalence of smoking, etc.
Polymorphisms Related to MI in the Screening Study (Men)
Gene Polymorphism Genetic Model P value
Platelet-activating factor acetylhydrolase G994T Additive < 0.001
p22phex
C242T Dominant 0.006
Connexin 37 C1019T Additive 0.007
Thrombospondin 4 G1186C Dominant 0.013
Angiotensinogen G-6A Recessive 0.019
Tumor necrosis factor α C-863A Dominant 0.045
Transforming growth factor β1 T869C Additive 0.049
G protein β3 subunit C825T Additive 0.051
Apolipoprotein C-III C-482T Recessive 0.057
Interleukin-10 T-819C Recessive 0.061
Thrombomodulin C2136T Additive 0.065
Apolipoprotein E C4070T Additive 0.074
Glycoprotein 1a A1648G Recessive 0.080
Interleukin-10 A-592C Recessive 0.088
Apolipoprotein G-219T Recessive 0.092
Thrombopoietin A59713G Recessive 0.094
Apolipoprotein C-III C1100T Recessive 0.095
CC Chemokine receptor 2 G190A Recessive 0.097
Endothelial Nitric Oxide Synthase T-786C Dominant 0.098
Adopted from: Yamada et al., Prediction of the Risk of Myocardial Infarction from Polymorphisms in Candidate
Genes. N Engl J Med 2002; 347: 1916-23.
Paraoxonase G584A Dominant 0.009
Interleukin-6 C-634G Additive 0.009
Connexin 37 C1019T Dominant 0.013
ATP-Binding Cassette Transporter I G1051A Additive 0.014
Tumor Necrosis factor α C-850T Additive 0.015
Endothelin-I G5665T Recessive 0.028
Apolipoprotein E C4070T Recessive 0.038
Apolipoprotein C-III C-482T Recessive 0.044
Apolipoprotein E T3932C Dominant 0.047
CD14 Receptor C-260T Additive 0.050
Tumor necrosis factor α G-238A Dominant 0.052
Plasminogen-activator inhibitor type I 4G-668/5G Recessive 0.055
Fatty-acid-binding protein 2 G2445A Additive 0.057
Insulin receptor substrate-I G3494A Dominant 0.058
Stromelysin-I 5A-1171/6A Additive 0.072
Glycoprotein Ibα C1018T Additive 0.072
E-selection A561C Dominant 0.074
Polymorphisms Related to MI in the Screening Study (Women)
Gene Polymorphism Genetic Model P value
Adopted from: Yamada et al., Prediction of the Risk of Myocardial Infarction from Polymorphisms in Candidate
Genes. N Engl J Med 2002; 347: 1916-23.
Distributions of Polymorphisms Associated with MI among
among the 4152 Subjects in the Large-Scale Study
Gene and polymorphism Controls Patents with MI
in %
Men (n=2858)
Connexin 37, C1019T at lp35.1
C/C 71.7 66.2
C/T 25.4 29.6
T/T 2.9 4.2
p22phex
, C242T at 16q24
C/C 75.9 80.7
C/T 22.5 17.9
T/T 1.5 1.4
Women (n=1294)
Plasminogen-activator inhibitor type 1
4G-668/5G at 7q21.3-q22
4G/4G 44.8 36.5
4G/5G 44.9 50.9
5G/5G 10.3 12.6
Stromelysin-1, 5A-1171/6A at 11q23
5A/5A 5.7 1.2
5A/6A 31.3 28.1
6A/6A 63.0 70.8
Adopted from: Yamada et al., Prediction of the Risk of Myocardial Infarction from Polymorphisms in Candidate
Genes. N Engl J Med 2002; 347: 1916-23.
 In men, MI was significantly associated with
the
C1019T polymorphism in the connexin 37 gene
(P<0.001).
 In women, the 4G-668/5G polymorphism in the
plasminogen-activator inhibitor type 1 gene
P<0.001) and the 5A-1171/6A polymorphism
Conclusions:
Determination of the genotypes of connexin 37,
plasminogen-activator inhibitor type 1,
and stromelysin-1 genes may prove reliable
in predicting the genetic risk of MI.
Questions:
• Knowing that 2-3 million gene polymorphisms
(SNP) exist, how many different SNPs do you
expect to be identified as risk markers of
arteriosclerosis and MI: >10 or >100 or >1000?
• Could there be certain polymorphisms
that protect people against atherosclerosis? Or
protect atherosclerotic subjects from
developing
myocardial infraction?
• Is it likely to find major gene polymorphisms
that could be responsible for 50-70% of MI
(like the 5 major traditional risk factors)?
• Is it likely that there are numerous
polymorphisms, each statistically significant,
in different populations?
• How closely do these genetic polymophisms
translate to functional proteomic variations?
Questions:
References
1.) Lu KP, Ramos KS. Identification of genes differentially expressed in vascular smooth muscle cells following
benzo[a]pyrene challenge: impli-cations for chemical atherogenesis. Biochem Biophys Res Commun. 1998;
253:828 –833.
2.) de Vries CJ, van Achterberg TA, Horrevoets AJ, ten Cate JW, Pannekoek H. Differential display identification of 40
genes with altered expression in activated human smooth muscle cells. Local expression in athero-sclerotic lesions of
smags, smooth muscle activation-specific genes. J Biol Chem. 2000;275:23939 –23947.
3.) Shiffman D, Mikita T, Tai JT, Wade DP, Porter JG, Seilhamer JJ, Somogyi R, Liang S, Lawn RM. Large scale gene
expression analysis of cholesterol-loaded macrophages. J Biol Chem. 2000;275:37324 –37332.
4.) Hiltunen MO, Niemi M, Yla-Herttuala S. Functional genomics and DNA array techniques in atherosclerosis research.
Curr Opin Lipidol. 1999;10: 515–519.
5.) McCaffrey TA, Fu C, Du B, Eksinar S, Kent KC, Bush H Jr, Kreiger K, Rosengart T, Cybulsky MI, Silverman ES, Collins
T. High-level expression of Egr-1 and Egr-1-inducible genes in mouse and human atherosclerosis. J Clin Invest. 2000;
105:653– 662.
6.) Tyson k.L., et al., Heterogeneity of gene expression in human atheroma unmasked using cDNA representational
difference analysis. Physiol Genomics. 2002: 9(2):121-30
7.) Faber BC et al., Identification of genes potentially involved in rupture of human atheroserotic plaques. Circ Res., 2001:
Sept 14:89(6):547-54.
8.) Faber BC et al., Genes potentially involved in plaque rupture. Curr Opin Lipidod. 2002. Oct;13 (5):545-52.
9 ) Ross R. Atherosclerosis: an inflammatory disease N Engl J Med. 1999; 340:115–126.
10.) Libby P. Changing concepts of atherogenesis. J Intern Med. 2000;247: 349–358.
11.) Broeckel U, Hengstenberg C, Mayer B, et al. A comprehensive linkage analysis for myocardial infarction and its related
risk factors. Nat Genet 2002;30:210-4.
12.) Cambien F, Poirier O, Lecerf L, et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent
risk factor for myocardial infarction. Nature 1992;359:641-4.
13.) Weiss EJ, Bray PF, Tayback M, et al. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for
coronary thrombosis.N Engl J Med 1996;334:1090-4.
14.) Iacoviello L, Di Castelnuovo A, de Knijff P, et al. Polymorphisms in the coagulation factor VII gene and the risk of
myocardial infarction. N Engl J Med 1998;338:79-85.
15.) Kuivenhoven JA, Jukema JW, Zwinderman AH, et al. The role of a common variant of the cholesteryl ester transfer
protein gene in the progression of coronary atherosclerosis. N Engl J Med 1998;338:86-93
16.) Ellsworth DL, Manolio TA. The emerging importance of genetics in epidemiologic research. II. Issues in study design
and gene mapping. Ann Epidemiol 1999;9:75-90
17.) Fu L et al., Relationship between gene polymorphism of the PAI-1 promoter and myocardial infraction.
Chin Med J (Engl) 2001. 1 Mar;114(3):266-9
18.) Tarashima M et al., Stromelysin promoter 5A/6A polymorphism is associated with acute myocardial infarction.
Circulation 1999 Jun 1;99(21):2717-9
19.) Kee F et al., Polymorphisms of the P-selectin gene and risk of myocardial infarction in men and women in the ECTIM
extension study. Etude cas-temoin de l'infarctus myocarde. Heart. 2000 Nov;84(5):548-52
20.) Yamada, Y et al., Prediction of the Risk of Myocardial Infarction from Polymorphisms in Candidate Genes. N Engl J Med
2002; 347: 1916-23.

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231 genetic marker(s) of mi

  • 1. Genetic Marker (s) Of MI – One, One Hundred, or One Thousand?! Provided by: M. Bidya Sagar, Ph.D. Structural Biology and Drug Discovery Laboratory Center for Vulnerable Plaque Research Texas Heart Institute Editorial Slides VP Watch – December 26, 2002 - Volume 2, Issue 51
  • 2.  Rupture prone vulnerable plaques are the predominant underlying process in the pathogenesis of acute coronary syndromes.  Although the morphology of these vulnerable plaques has been studied extensively, the underlying genetic markers of these plaques and patients in whom vulnerable plaque develop, suffer a fatal cardiovascular event, are largely unknown.
  • 3. • Genomic and Proteomic research may shed light on the way to discover these markers of plaque/patient vulnerability. • Human Genome studies are underway to identify: – differential expression of up- and down-regulated genes in plaque vs normal arterial walls, and comparison of the mRNA expression at different stages of plaque development. – single nucleotide polymorphism (SNP) among cardiovascular disease patients vs. normal subjects. – loci on chromosomes through linkage studies
  • 4. Several studies compared the gene expression of : • activated human umbilical vein endothelial cells • vascular smooth muscle cells • cholesterol-loaded macrophages with that of nonactivated cells.1-3 1-Gene Expression Studies in Plaque
  • 5.  Studies in cell lines revealed differential regulation of genes involved in leukocyte trafficking, cell-cycle control, and apoptosis.  Differences in gene expression have been observed among fatty streaks and advanced lesions 4 and intima and media of human atherosclerotic plaques. 5 1- Gene Expression Studies in Plaque
  • 6.  Tyson et al studied heterogeneity of gene expression in human atheroma using cDNA analysis. 6  Faber et al have suggested perilipine, as well as other genes potentially involved in rupture of human atherosclerotic plaques.7-8 1- Gene Expression Studies in Plaque
  • 7.  Genetic-linkage studies 11 and candidate gene analyses 12-16 have implicated a locus and several genes related to predisposition to myocardial infraction.  A linkage analysis for myocardial infarction and its related risk factors was carried out by Broecke et al. 11 2- Genetic Linkage Studies
  • 8.  They have scanned the whole genome in 513 families to identify chromosomal regions linked to MI  They showed the risk of MI maps to a single region on chromosome 14 with a significant lod score of 3.9 (pointwise P=0.00015, genome-wide P<0.05). 2- Genetic Linkage Studies
  • 9.  Human Genome mapping has led to a massive search for clinically relevant genomic information: including (SNPs), which consist of substitutions of one nucleotide for another in a DNA sequence.  Human genomes are 99.9% identical with only 0.1% of the genome showing polymorphisms.9-10 3- Gene Polymorphism (SNP) Studies
  • 10.  About 2-3 million SNPs have been found in exonic, intronic, regulatory, and intergenic regions.9-10  Though almost all genes contain SNPs, only a minority of SNPs result in amino acid variation in proteins. 9-10 3- Gene Polymorphism (SNP) Studies
  • 11.  Myocardial infarction is a complex multifactorial and polygenic disorder; and therefore, it may not be possible to find an specific genetic make-up predicting the disease.  Genetic polymorphisms have been associated with myocardial infarction and angina pectoris. 20 3- Gene Polymorphism (SNP) Studies
  • 12.  Fu L et al., investigated the association between gene polymorphism of the plasminogen activator inhibitor-1 (PAI-1) and MI in a Chinese population.17  The 5A/6A polymorphism in the promoter of the stromelysin gene has been identified as a novel pathogenetic risk factor for MI. 18  Polymorphisms of the P-selectin gene and risk of MI in men and women has been reported.19 Gene Polymorphism (SNP) Studies
  • 13.  As reported in VP Watch of this week, Yamada et al., published in the New England Journal of Medicine, discovery of new polymorphisms in candidate genes that confer susceptibility to myocardial infarction. 20
  • 14. Method:  A fluorescence- or colorimetry-based allele- specific DNA-primer-probe assay  To determine Genotypes of 112 polymorphisms of 71 candidate genes in 2819 unrelated Japanese patients with MI (2003 men and 816 women) and 2242 unrelated Japanese controls (1306 men and 936 women).
  • 15. Results:  Screening of the 112 polymorphisms for an association with MI in 909 subjects.  19 polymorphisms were selected in men and 18 in women by means of logistic-regression analysis, after adjustment for age, BMI, the prevalence of smoking, etc.
  • 16. Polymorphisms Related to MI in the Screening Study (Men) Gene Polymorphism Genetic Model P value Platelet-activating factor acetylhydrolase G994T Additive < 0.001 p22phex C242T Dominant 0.006 Connexin 37 C1019T Additive 0.007 Thrombospondin 4 G1186C Dominant 0.013 Angiotensinogen G-6A Recessive 0.019 Tumor necrosis factor α C-863A Dominant 0.045 Transforming growth factor β1 T869C Additive 0.049 G protein β3 subunit C825T Additive 0.051 Apolipoprotein C-III C-482T Recessive 0.057 Interleukin-10 T-819C Recessive 0.061 Thrombomodulin C2136T Additive 0.065 Apolipoprotein E C4070T Additive 0.074 Glycoprotein 1a A1648G Recessive 0.080 Interleukin-10 A-592C Recessive 0.088 Apolipoprotein G-219T Recessive 0.092 Thrombopoietin A59713G Recessive 0.094 Apolipoprotein C-III C1100T Recessive 0.095 CC Chemokine receptor 2 G190A Recessive 0.097 Endothelial Nitric Oxide Synthase T-786C Dominant 0.098 Adopted from: Yamada et al., Prediction of the Risk of Myocardial Infarction from Polymorphisms in Candidate Genes. N Engl J Med 2002; 347: 1916-23.
  • 17. Paraoxonase G584A Dominant 0.009 Interleukin-6 C-634G Additive 0.009 Connexin 37 C1019T Dominant 0.013 ATP-Binding Cassette Transporter I G1051A Additive 0.014 Tumor Necrosis factor α C-850T Additive 0.015 Endothelin-I G5665T Recessive 0.028 Apolipoprotein E C4070T Recessive 0.038 Apolipoprotein C-III C-482T Recessive 0.044 Apolipoprotein E T3932C Dominant 0.047 CD14 Receptor C-260T Additive 0.050 Tumor necrosis factor α G-238A Dominant 0.052 Plasminogen-activator inhibitor type I 4G-668/5G Recessive 0.055 Fatty-acid-binding protein 2 G2445A Additive 0.057 Insulin receptor substrate-I G3494A Dominant 0.058 Stromelysin-I 5A-1171/6A Additive 0.072 Glycoprotein Ibα C1018T Additive 0.072 E-selection A561C Dominant 0.074 Polymorphisms Related to MI in the Screening Study (Women) Gene Polymorphism Genetic Model P value Adopted from: Yamada et al., Prediction of the Risk of Myocardial Infarction from Polymorphisms in Candidate Genes. N Engl J Med 2002; 347: 1916-23.
  • 18. Distributions of Polymorphisms Associated with MI among among the 4152 Subjects in the Large-Scale Study Gene and polymorphism Controls Patents with MI in % Men (n=2858) Connexin 37, C1019T at lp35.1 C/C 71.7 66.2 C/T 25.4 29.6 T/T 2.9 4.2 p22phex , C242T at 16q24 C/C 75.9 80.7 C/T 22.5 17.9 T/T 1.5 1.4 Women (n=1294) Plasminogen-activator inhibitor type 1 4G-668/5G at 7q21.3-q22 4G/4G 44.8 36.5 4G/5G 44.9 50.9 5G/5G 10.3 12.6 Stromelysin-1, 5A-1171/6A at 11q23 5A/5A 5.7 1.2 5A/6A 31.3 28.1 6A/6A 63.0 70.8 Adopted from: Yamada et al., Prediction of the Risk of Myocardial Infarction from Polymorphisms in Candidate Genes. N Engl J Med 2002; 347: 1916-23.
  • 19.  In men, MI was significantly associated with the C1019T polymorphism in the connexin 37 gene (P<0.001).  In women, the 4G-668/5G polymorphism in the plasminogen-activator inhibitor type 1 gene P<0.001) and the 5A-1171/6A polymorphism
  • 20. Conclusions: Determination of the genotypes of connexin 37, plasminogen-activator inhibitor type 1, and stromelysin-1 genes may prove reliable in predicting the genetic risk of MI.
  • 21. Questions: • Knowing that 2-3 million gene polymorphisms (SNP) exist, how many different SNPs do you expect to be identified as risk markers of arteriosclerosis and MI: >10 or >100 or >1000? • Could there be certain polymorphisms that protect people against atherosclerosis? Or protect atherosclerotic subjects from developing myocardial infraction?
  • 22. • Is it likely to find major gene polymorphisms that could be responsible for 50-70% of MI (like the 5 major traditional risk factors)? • Is it likely that there are numerous polymorphisms, each statistically significant, in different populations? • How closely do these genetic polymophisms translate to functional proteomic variations? Questions:
  • 23. References 1.) Lu KP, Ramos KS. Identification of genes differentially expressed in vascular smooth muscle cells following benzo[a]pyrene challenge: impli-cations for chemical atherogenesis. Biochem Biophys Res Commun. 1998; 253:828 –833. 2.) de Vries CJ, van Achterberg TA, Horrevoets AJ, ten Cate JW, Pannekoek H. Differential display identification of 40 genes with altered expression in activated human smooth muscle cells. Local expression in athero-sclerotic lesions of smags, smooth muscle activation-specific genes. J Biol Chem. 2000;275:23939 –23947. 3.) Shiffman D, Mikita T, Tai JT, Wade DP, Porter JG, Seilhamer JJ, Somogyi R, Liang S, Lawn RM. Large scale gene expression analysis of cholesterol-loaded macrophages. J Biol Chem. 2000;275:37324 –37332. 4.) Hiltunen MO, Niemi M, Yla-Herttuala S. Functional genomics and DNA array techniques in atherosclerosis research. Curr Opin Lipidol. 1999;10: 515–519. 5.) McCaffrey TA, Fu C, Du B, Eksinar S, Kent KC, Bush H Jr, Kreiger K, Rosengart T, Cybulsky MI, Silverman ES, Collins T. High-level expression of Egr-1 and Egr-1-inducible genes in mouse and human atherosclerosis. J Clin Invest. 2000; 105:653– 662. 6.) Tyson k.L., et al., Heterogeneity of gene expression in human atheroma unmasked using cDNA representational difference analysis. Physiol Genomics. 2002: 9(2):121-30 7.) Faber BC et al., Identification of genes potentially involved in rupture of human atheroserotic plaques. Circ Res., 2001: Sept 14:89(6):547-54. 8.) Faber BC et al., Genes potentially involved in plaque rupture. Curr Opin Lipidod. 2002. Oct;13 (5):545-52. 9 ) Ross R. Atherosclerosis: an inflammatory disease N Engl J Med. 1999; 340:115–126. 10.) Libby P. Changing concepts of atherogenesis. J Intern Med. 2000;247: 349–358. 11.) Broeckel U, Hengstenberg C, Mayer B, et al. A comprehensive linkage analysis for myocardial infarction and its related risk factors. Nat Genet 2002;30:210-4. 12.) Cambien F, Poirier O, Lecerf L, et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992;359:641-4. 13.) Weiss EJ, Bray PF, Tayback M, et al. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis.N Engl J Med 1996;334:1090-4. 14.) Iacoviello L, Di Castelnuovo A, de Knijff P, et al. Polymorphisms in the coagulation factor VII gene and the risk of myocardial infarction. N Engl J Med 1998;338:79-85. 15.) Kuivenhoven JA, Jukema JW, Zwinderman AH, et al. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. N Engl J Med 1998;338:86-93 16.) Ellsworth DL, Manolio TA. The emerging importance of genetics in epidemiologic research. II. Issues in study design and gene mapping. Ann Epidemiol 1999;9:75-90 17.) Fu L et al., Relationship between gene polymorphism of the PAI-1 promoter and myocardial infraction. Chin Med J (Engl) 2001. 1 Mar;114(3):266-9 18.) Tarashima M et al., Stromelysin promoter 5A/6A polymorphism is associated with acute myocardial infarction. Circulation 1999 Jun 1;99(21):2717-9 19.) Kee F et al., Polymorphisms of the P-selectin gene and risk of myocardial infarction in men and women in the ECTIM extension study. Etude cas-temoin de l'infarctus myocarde. Heart. 2000 Nov;84(5):548-52 20.) Yamada, Y et al., Prediction of the Risk of Myocardial Infarction from Polymorphisms in Candidate Genes. N Engl J Med 2002; 347: 1916-23.