Background Although epidemiologic studies have suggested thatseveral genetic variants increase the risk of myocardial infarction,large-scale association studies that examine many polymorphismssimultaneously are required to allow reliable prediction ofthe genetic risk of myocardial infarction.
Methods We used a fluorescence- or colorimetry-based allele-specificDNA-primer–probe assay system to determine the genotypesof 112 polymorphisms of 71 candidate genes in 2819 unrelatedJapanese patients with myocardial infarction (2003 men and 816women) and 2242 unrelated Japanese controls (1306 men and 936women).
Results In an initial screening of the 112 polymorphisms foran association with myocardial infarction in 909 subjects, 19polymorphisms were selected in men and 18 in women by meansof logistic-regression analysis, after adjustment for age, body-massindex, and the prevalence of smoking, hypertension, diabetesmellitus, hypercholesterolemia, and hyperuricemia. In a large-scalestudy involving the selected polymorphisms and the remaining4152 subjects, similar logistic-regression analysis revealedthat the risk of myocardial infarction was significantly associatedwith the C1019T polymorphism in the connexin 37 gene (P<0.001)in men and the 4G–668/5G polymorphism in the plasminogen-activatorinhibitor type 1 gene (P<0.001) and the 5A–1171/6Apolymorphism in the stromelysin-1 gene (P<0.001) in women.
Conclusions Determination of the genotypes of the connexin 37,plasminogen-activator inhibitor type 1, and stromelysin-1 genesmay prove reliable in predicting the genetic risk of myocardialinfarction and might thus contribute to the primary preventionof this condition.
Myocardial infarction is a complex multifactorial and polygenicdisorder that is thought to result from an interaction betweena person's genetic makeup and various environmental factors.1,2In general, the incidence of myocardial infarction increasesadditively as a function of the number of conventional riskfactors, including hypertension, diabetes mellitus, and hypercholesterolemia.2Although each risk factor itself is partly under genetic control,a family history of myocardial infarction is also an independentpredictor, suggesting the existence of additional susceptibilitygenes for this condition.1 Furthermore, some patients who havehad a myocardial infarction do not have any conventional riskfactors, suggesting the contribution of an uncharacterized geneticcomponent. Given that myocardial infarction is a leading causeof death in the Western world and markedly impairs the qualityof life by causing heart failure or refractory arrhythmias,prevention of this disease is an important public health goal.One approach to preventing this condition is to identify disease-susceptibilitygenes. Genetic-linkage studies3 and candidate-gene analyses4,5,6,7have implicated a locus and several candidate genes in the predispositionto myocardial infarction. Although epidemiologic studies haverevealed that several genetic variants, including those of angiotensin-convertingenzyme,4 platelet glycoprotein IIIa,5 coagulation factor VII,6and cholesterol-ester transfer protein,7 increase the risk ofmyocardial infarction, the results of these studies remain controversial,with no consensus on their implications. In addition, becauseof racial and ethnic differences in genetic polymorphisms, itis important to construct a data base of polymorphisms relatedto myocardial infarction in each racial and ethnic group.
The purpose of the present study was to identify polymorphismsthat confer susceptibility to myocardial infarction and therebyto contribute to the primary prevention of this condition.
Methods
Study Population
The study population comprised 5061 unrelated Japanese subjects(3309 men and 1752 women) who either visited outpatient clinicsof or were admitted to 1 of the 15 participating hospitals (seethe Appendix) between July 1994 and December 2001. The 2819patients with myocardial infarction (2003 men and 816 women)all underwent coronary angiography and left ventriculography.The diagnosis of myocardial infarction was based on typicalelectrocardiographic changes and increased serum activitiesof enzymes such as creatine kinase, aspartate aminotransferase,and lactate dehydrogenase. The diagnosis was confirmed by thepresence of wall-motion abnormality on left ventriculographyand attendant stenosis in any of the major coronary arteriesor in the left main trunk, as documented by coronary angiography.
The 2242 control subjects (1306 men and 936 women) were recruitedfrom persons found to have at least one of the conventionalrisk factors for coronary artery disease, including habitualcigarette smoking (10 or more cigarettes daily), obesity (abody-mass index [the weight in kilograms divided by the squareof the height in meters] of at least 26), hypertension (definedby a systolic blood pressure of at least 140 mm Hg, a diastolicblood pressure of at least 90 mm Hg, or both), diabetes mellitus(defined by a blood glucose level of at least 126 mg per deciliter[6.93 mmol per liter] after an overnight fast, a glycosylatedhemoglobin value of at least 6.5 percent, or both), hypercholesterolemia(serum total cholesterol level of at least 220 mg per deciliter[5.72 mmol per liter]), or hyperuricemia (serum uric acid levelof at least 7.7 mg per deciliter [0.46 mmol per liter] for menand at least 5.5 mg per deciliter [0.33 mmol per liter] forwomen), but who had no history of coronary artery disease. Theyhad normal electrocardiograms at rest and no signs of myocardialischemia on exercise stress testing. The study protocol wasapproved by the committees on the ethics of human research ofNagoya University Graduate School of Medicine and Gifu InternationalInstitute of Biotechnology, and written informed consent wasobtained from each participant.
Selection of Polymorphisms
With the use of public data bases, including PubMed and OnlineMendelian Inheritance in Man, we selected 71 candidate genesthat have been characterized and potentially associated withcoronary atherosclerosis or vasospasm, hypertension, diabetesmellitus, or hyperlipidemia on the basis of a comprehensiveoverview of vascular biology, platelet and leukocyte biology,coagulation and fibrinolysis cascades, as well as lipid andglucose metabolism and other metabolic factors. We further selected112 polymorphisms of these genes — most of which werein the promoter regions, exons, or splice-donor or splice-acceptorsites in introns — that might be expected to cause changesin the function or level of expression of the encoded protein(Table 1). The minus signs before the numbered nucleotide insome polymorphisms, such as C–535T in Table 1, refer tothe 5' upstream region relative to the transcription-initiationsite of a gene.
Table 1. The 112 Polymorphisms Examined in the Screening Study.
Genotyping of Polymorphisms
Venous blood (7 ml) was collected from each subject into tubescontaining 50 mmol of EDTA per liter, and genomic DNA was isolatedwith a kit (Qiagen). Genotypes of the 112 polymorphisms weredetermined with a fluorescence- or colorimetry-based allele-specificDNA-primer–probe assay system (Toyobo Gene Analysis) (describedin detail in Supplementary Appendix 1, available with the fulltext of this article at http://www.nejm.org). Polymorphic regionsof each gene were amplified by the polymerase chain reaction(PCR) with two allele-specific sense (or antisense) primerslabeled at the 5' end with either fluorescein isothiocyanateor Texas red and an antisense (or sense) primer labeled at the5' end with biotin. Alternatively, the polymorphic regions wereamplified with two allele-specific sense (or antisense) primersand a biotin-labeled antisense (or sense) primer or with a senseprimer and a biotin-labeled antisense primer. The reaction mixture(25 µl) contained 20 ng of DNA, 5 pmol of each primer,0.2 mmol of each deoxynucleoside triphosphate per liter, 1 to4 mmol of magnesium chloride per liter, and 1 U of DNA polymerase(rTaq or KODplus, Toyobo) in corresponding DNA polymerase buffer.The amplification protocol comprised an initial period of denaturationat 95°C for 5 minutes, 35 to 45 cycles of denaturation at95°C for 30 seconds, annealing at 55° to 67.5°Cfor 30 seconds, extension at 72°C for 30 seconds, and afinal period of extension at 72°C for 2 minutes.
To determine the genotype by means of fluorescence, we incubatedamplified DNA with streptavidin-conjugated magnetic beads in96-well plates at room temperature. The plates were placed ona magnetic stand, and the supernatants were then transferredto the wells of the 96-well plate containing 10 mmol of sodiumhydroxide per liter and assessed for fluorescence at excitationand emission wavelengths of 485 and 538 nm, respectively, inthe case of fluorescein isothiocyanate and of 584 and 612 nm,respectively, in the case of Texas red. To determine the genotypeby means of colorimetry, we denatured amplified DNA with 0.3mol of sodium hydroxide per liter and subjected it to hybridizationat 37°C for 30 minutes in hybridization buffer containing30 to 45 percent formamide with each of two allele-specificcapture probes fixed to the bottom of the wells of a 96-wellplate. After thorough washing of the wells, alkaline phosphatase–conjugatedstreptavidin was added to each well and the plate was incubatedat 37°C for 15 minutes while being agitated. The wells wereagain washed, and after the addition of a solution containing0.8 mmol of 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium(monosodium salt) per liter and 0.4 mmol of 5-bromo-4-chloro-3-indolylphosphate p-toluidine salt per liter, the absorbance of thesamples was assessed at a wavelength of 450 nm.
To confirm the accuracy of genotyping with the use of this method,we randomly selected 50 DNA samples and subjected them to PCRand restriction-fragment–length polymorphism analysisor to direct DNA sequencing of the PCR products. In each instance,the genotype determined by the allele-specific DNA-primer–probeassay system was identical to that determined by the confirmatorymethods.
Association Study
We first performed a screening study using the 112 polymorphismsof the 71 candidate genes to screen 909 subjects who were randomlyselected from the total study population of 5061 subjects. Inthis screening study, the cutoff P value was defined as lessthan 0.1 for multivariate logistic-regression analysis involvingdominant, recessive, or additive genetic models in order toavoid false negative associations. From the screening study,we selected 19 polymorphisms related to myocardial infarctionin men and 18 related to myocardial infarction in women. Wethen performed a large-scale study to assess the associationbetween these polymorphisms and the risk of myocardial infarctionin the remaining 4152 study subjects. An association was consideredsignificant at a P value of less than 0.001 on multivariatelogistic-regression analysis.
Statistical Analysis
Measured variables were compared between patients with myocardialinfarction and controls with use of the unpaired Student's t-testor Mann–Whitney U test. Categorical variables were comparedwith use of the chi-square test. Allele frequencies were estimatedby the gene-counting method, and the chi-square test was usedto identify departures from Hardy–Weinberg equilibrium.We performed multivariate logistic-regression analysis to adjustrisk factors, with myocardial infarction as a dependent variableand independent variables that included age, body-mass index,smoking status (a value of 0 assigned for a nonsmoker and 1for a smoker), metabolic variables (a value of 0 assigned forthe absence of a history of hypertension, diabetes mellitus,hypercholesterolemia, or hyperuricemia and a value of 1 forthe presence of such a history), and the genotype of each polymorphism.Each genotype was assessed with the use of dominant, recessive,and additive genetic models, and the P value, odds ratio, and95 percent confidence interval were calculated.
Results
The characteristics of the 909 subjects in the screening studyfor the 112 polymorphisms are shown in Table 2. Among the men,there were no significant differences in age, body-mass index,or the prevalence of conventional risk factors for coronaryartery disease, including smoking, hypertension, diabetes mellitus,hypercholesterolemia, and hyperuricemia, between patients withmyocardial infarction and controls. For women, age, body-massindex, and the prevalence of hypertension, hypercholesterolemia,and hyperuricemia did not differ significantly between patientswith myocardial infarction and controls, but the prevalenceof both smoking and diabetes mellitus was higher among patientswith myocardial infarction than among controls. On the basisof multivariate logistic-regression analysis with adjustmentfor age, body-mass index, and the prevalence of smoking, hypertension,diabetes mellitus, hypercholesterolemia, and hyperuricemia,19 polymorphisms were selected for further study in men and18 for further study in women (Table 3). Only four of thesepolymorphisms were observed in both sexes.
Table 3. Polymorphisms Related to Myocardial Infarction in the Screening Study.
The characteristics of all 4152 subjects in the large-scalestudy are shown in Table 4. For men, age, body-mass index, andthe prevalence of smoking did not differ significantly betweenpatients with myocardial infarction and controls; the prevalenceof both hypertension and hyperuricemia was lower and that ofboth diabetes mellitus and hypercholesterolemia was higher amongpatients than controls. For women, age and the prevalence ofboth hypertension and hyperuricemia did not differ significantlybetween patients with myocardial infarction and controls; body-massindex and the prevalence of smoking, diabetes mellitus, andhypercholesterolemia were greater among patients than controls.In the large-scale study of 19 polymorphisms in men and 18 polymorphismsin women, multivariate logistic-regression analysis with adjustmentfor age, body-mass index, and the prevalence of smoking, hypertension,diabetes mellitus, hypercholesterolemia, and hyperuricemia revealedthat one polymorphism (the replacement of cytosine with thymineat position 1019 [C1019T] in the connexin 37 gene) was associatedwith a significant risk of myocardial infarction in men andtwo polymorphisms (the replacement of four guanines with fiveguanines at position –668 [4G–668/5G] in the plasminogen-activatorinhibitor type 1 gene and the replacement of five adenines withsix adenines at position –1171 [5A– 1171/6A] inthe stromelysin-1 gene) were associated with a significant riskof myocardial infarction in women (P<0.001 for all comparisonswith the use of either a dominant or a recessive genetic model)(Table 5). The replacement of cytosine with thymine at position242 in the p22phox gene was also potentially associated witha risk of myocardial infarction in men (P<0.01). The genotypicdistributions of these polymorphisms are shown in Table 6 andwere in Hardy–Weinberg equilibrium.
Table 6. Distributions of Polymorphisms Associated with Myocardial Infarction among the 4152 Subjects in the Large-Scale Study.
Discussion
We examined the relation of 112 polymorphisms in 71 candidategenes to the risk of myocardial infarction. Our large-scalestudy, involving 4152 subjects, revealed that the C1019T polymorphismin the connexin 37 gene was associated with a significant riskof myocardial infarction in men and that the 4G–668/5Gpolymorphism in the plasminogen-activator inhibitor type 1 geneand the 5A–1171/6A polymorphism in the stromelysin-1 genewere associated with a significant risk of myocardial infarctionin women.
Many studies have examined the relations between polymorphismsand coronary artery disease or myocardial infarction. The resultsof most of these studies, however, remain controversial, withno consensus on their implications, mainly because of the limitedsize of the study populations, the ethnic diversity of polymorphisms,and complicating environmental factors. The chief cause of myocardialinfarction is atherosclerotic coronary artery disease, whichcontributes to hemodynamically significant narrowing of thearterial lumen, alters the control of vasomotor tone, and increasesthe likelihood that plaque will be disrupted and thrombi willform. We thus selected 71 candidate genes on the basis of acomprehensive overview of vascular biology, platelet and leukocytebiology, coagulation, and fibrinolysis systems, as well as lipidand glucose metabolism and other metabolic factors. Indeed,genes associated with myocardial infarction may have roles invarious aspects of the pathogenesis of this condition, includinggap-junctional communication between vascular endothelial cells(connexin 37),8,9,10 the production of reactive oxygen speciesby vascular smooth-muscle cells (p22phox),11,12,13,14 fibrinolysis(plasminogen-activator inhibitor type 1),15,16,17 and matrixmetabolism (stromelysin-1).18,19,20,21 We examined 112 polymorphismsin 909 subjects, 19 polymorphisms in 2858 men, and 18 polymorphismsin 1294 women, resulting in the determination of 179,402 genotypesand possibly representing the largest such association studyof polymorphisms to date.
The C1019T polymorphism of the connexin 37 gene was associatedwith thickening of the carotid intima in Swedish men, with theC allele being overrepresented in men with atherosclerotic plaques.9The C allele of this gene was also associated with coronaryartery disease in a Taiwanese population.10 However, both thesestudies were small, and in contrast to their findings, our resultssuggest that the T allele of this polymorphism is a risk factorfor myocardial infarction in men.
The 4G allele of the plasminogen-activator inhibitor type 1gene was associated with myocardial infarction in a small groupof Swedish men.15 Large studies of men in the United States16and of white women in the Netherlands,17 however, did not confirmsuch an association. Furthermore, the 4G/4G genotype was associatedwith a lower risk of death from cerebrovascular causes thanwas the 5G/5G genotype in the latter study.17 Our results suggestthat the 5G allele is a risk factor for myocardial infarctionin women, a view consistent with the latter observation.
The 6A allele of the stromelysin-1 gene was associated withan increased rate of progression of coronary atherosclerosisin a small population of men in England.18 The 6A/6A genotypewas also associated with an increased intima–media thicknessof the carotid artery in Finnish men20 and in men and womenin New York.21 We found that the 6A allele is a risk factorfor myocardial infarction in women, consistent with these previousobservations.
In our large-scale study, neither of the polymorphisms thatwere associated with a significant risk of myocardial infarctionin women was associated with a significant risk of this conditionin men. The reason for this difference remains unclear. In Japan,the incidence of myocardial infarction is low in women, especiallyamong premenopausal women, probably because such women are protectedby their high serum level of estrogen.22 Indeed, most womenwith myocardial infarction in our study were postmenopausal.The sex-based difference in the association between geneticpolymorphisms and the risk of myocardial infarction might thusbe attributable, at least in part, to the differences in thelevels of estrogen or other hormones between men and women.
Our results indicate that the identification of genotypes ofplasminogen-activator inhibitor type 1 and stromelysin-1, especiallythe latter, given its high odds ratio of 4.7 (for the comparisonof the 5A/6A plus 6A/6A genotypes with the 5A/5A genotype),may prove to be a reliable means of predicting the genetic riskof myocardial infarction in women and might thus contributeto the primary prevention of this condition. For men, however,although a polymorphism of the connexin 37 gene was associatedwith a significant risk of myocardial infarction, the odds ratiowas only 1.4 (for the comparison of the C/T plus T/T genotypeswith the C/C genotype). Further studies are thus required inmen to identify additional polymorphisms that are associatedwith a significant risk of myocardial infarction and that havehigher odds ratios.
Supported in part by a Grant-in-Aid for Scientific Researchfrom the Ministry of Education, Science, Sports, and Cultureof Japan (to Dr. Yokota) and by grants from Gifu Life ScienceResearch Foundation, Japan Cardiovascular Research Foundation,and Takeda Science Foundation (all to Dr. Yamada).
Source Information
From the Department of Gene Therapy, Gifu International Institute of Biotechnology, Mitake (Y.Y., M.T.); the Cardiovascular Division, Department of Pathophysiology, Nagoya University Graduate School of Medicine, Nagoya (H. Izawa, S.I., M.Y.); the Division of Cardiology, Kosei Hospital, Anjo (F.T.); the Division of Cardiology, Okazaki City Hospital, Okazaki (H. Ishihara); the Cardiovascular Center, Nagoya Daini Red Cross Hospital, Nagoya (H.H.); and the Department of Cardiology, Ogaki Municipal Hospital, Ogaki (T.S.) — all in Japan.
Address reprint requests to Dr. Yokota at the Department of Clinical Laboratory Medicine, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan, or at myokota{at}med.nagoya-u.ac.jp.
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Appendix
In addition to the authors, the following investigators andJapanese institutions participated in the study: Kosei Hospital,Anjo — H. Horibe, M. Watarai, K. Takemoto, and S. Shimizu;Okazaki City Hospital, Okazaki — A. Hirashiki, Y. Murase,and Y. Suzuki; Nagoya Daini Red Cross Hospital, Nagoya —Y. Yoshida and T. Okada; Nagoya University Hospital, Nagoya— R. Ishiki, F. Somura, A. Yamada, and T. Kato; OgakiMunicipal Hospital, Ogaki — K. Takagi; Hamamatsu MedicalCenter, Hamamatsu — C. Takanaka; Chita City Hospital,Chita — M. Maeda and Y. Nishinaka; Hekinan City Hospital,Hekinan — T. Fukumitsu; Nagoya East City Hospital, Nagoya— H. Kanda; Nagoya National Hospital, Nagoya — T.Watanabe; Showa Hospital, Konan — S. Ishikawa and F. Saito;Toyota Memorial Hospital, Toyota — H. Inagaki and S. Kamihara;Tokai Central Hospital, Kagamihara — S. Ogawa and T. Fujimura;National Chubu Hospital, Obu — J. Goto; and Marine Clinic,Nagoya — S. Kato.
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