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(Circulation. 2002;105:2943.)
© 2002 American Heart Association, Inc.
Brief Rapid Communications |
From EA 3516 (F.F., D.B.), Faculté de Médecine Xavier Bichat, Paris, France; INSERM U525 (V.N., F.C.), Paris, France; MONICA Project (A.E., F.K.), Belfast, Northern Ireland, UK; MONICA Project (J.-B.R.), Haute-Garonne, Toulouse, France; MONICA Project (D.A.), Bas-Rhin, Strasbourg, France; and MONICA Project (G.L.), Lille, France.
Correspondence to Frédéric Fumeron, EA 3516, Faculté de Médecine Xavier Bichat, BP416, 16 rue Henri Huchard, 75870 Paris Cedex 18, France.
| Abstract |
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Methods and Results The SLC6A4 polymorphism has been investigated by polymerase chain reaction in 671 male patients with MI and in 688 controls from the Etude Cas-Témoins de lInfarctus du Myocarde (ECTIM) multicentric study. Percentages for LL, LS, and SS genotypes were 35.5%, 45.4%, and 19.1%, respectively, for cases versus 28.1%, 49.1%, and 22.8%, respectively, for controls. S allele frequency was 41.8% and 47.4% for cases and controls, respectively. After adjustment for age and center by using multivariable logistic regression, the odds ratio for MI associated with the LL genotype was 1.40 (95% CI 1.11 to 1.76, P=0.0047).
Conclusions The LL genotype of the SLC6A4 polymorphism is associated with a higher risk of MI. This could be attributable to the effect of the polymorphism on serotonin-mediated platelet activation or smooth muscle cell proliferation or on other risk factors, such as depression or response to stress.
Key Words: serotonin transporter genes myocardial infarction risk factors
| Introduction |
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A polymorphism in the promoter region of the SLC6A4 gene has been described.3 This polymorphism is located
1 kb upstream from the transcription initiation site and consists of a 44-bp insertion or deletion. This polymorphism has been demonstrated to be functional in vitro.3,4 The transcriptional activity of the long variant is more than twice that of the short variant. At the protein level, membrane preparations from LL lymphoblasts bind 30% to 40% more of a labeled marker than do membranes from LS or SS cells. Uptake of labeled 5-HT in LL cells is
2 times that in cells carrying the S variant. The research of associations between this polymorphism and personality traits or psychiatric diseases has yielded conflicting results.4,5 However, we have found an association between the S allele and anorexia nervosa and lower food intake in normal or overweight subjects.6 Thus, the effect of the S allele appears to be quite similar to that of serotonergic anorectic drugs inhibiting the reuptake of 5-HT.
We hypothesized that this polymorphism involved in the 5-HT pathway could be a good candidate in the predisposition to MI, and the aim of the present study was to test this hypothesis in Etude Cas-Témoins de lInfarctus du Myocarde (ECTIM), a case-control study of MI.
| Methods |
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Genomic DNA was prepared from white blood cells by phenol extraction. The polymorphism of the promoter of the SLC6A4 gene was analyzed by polymerase chain reaction amplification.9
Effects of genotypes on the risk of MI adjusted for age and center were analyzed by multiple logistic regression. The first model tested was an effect of LL by reference to LS and SS genotypes combined, according to the in vitro functional data. In a second model, LL and LS were tested by reference to SS to estimate a possible gene-dosage effect. Effects of genotypes on continuous parameters were analyzed by ANOVA.
| Results |
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| Discussion |
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The lower transcriptional efficiency of the S allele provokes an inhibition of the uptake of 5-HT in vitro. This is highly concordant with the results indicating a protective effect of the SSRIs against MI.2 The SSRIs could be protective either by an effect on depression or stress as risk factors for MI or by inhibiting 5-HTmediated platelet activation. As for SSRIs, a question arises about the mechanism involved in the modulation in MI risk by the SLC6A4 polymorphism.
A depression-mediated mechanism is compatible with the effects of this polymorphism observed on personality traits or mood disorders in some studies.4 However, these effects are not always reported.5 The response to stress has also been explored with regard to the SLC6A4 polymorphism. Persons with the L allele exhibited greater blood pressure and heart rate responses to a mental stress protocol as well as higher levels in cerebrospinal fluid of 5-hydroxyindolacetic acid, a 5-HT metabolite.11 No effect of the polymorphism on blood pressure was observed in the ECTIM study, but such an influence could appear only in conditions of stress.
It has already been shown that the S allele of the polymorphism, which decreased the number of 5-HT transporters, inhibited the uptake of 5-HT by platelets.12 A similar effect has been observed with SSRIs. In elderly depressed patients, the LL genotype has been associated with an increase in platelet activation,13 which could lead to a greater release of 5-HT in response to subclinical vascular damage. 5-HT has a potent influence on the arterial wall and is associated with coronary artery disease.14 In normal human coronary arteries, 5-HT induces vasodilatation. In the presence of endothelial dysfunction, 5-HT induces vasoconstriction.15 5-HT also induces vascular smooth muscle cell proliferation.1618 Blood 5-HT levels are higher in L carriers,19 and pulmonary artery smooth muscle cells with the LL genotype are more proliferative in response to 5-HT than are those of other genotypes.20 The proliferation of smooth muscle cells is a part of the atherosclerotic process and could be a deleterious effect of the LL genotype, affecting the risk of MI.
Another potential mechanism could be the effect on food intake. We have previously evidenced an effect on anorexia nervosa and also an effect on food intake in subjects at a normal weight and in obese subjects.6 The S allele was associated with a lower food intake of all nutrients, including fats, which theoretically could protect an individual from heart disease. However, because the polymorphism did not influence blood lipids or BMI in the ECTIM study, the causal role of this relationship is unlikely.
The ECTIM study allows conclusions to be drawn only for nonfatal MI. A prospective study is required to obtain information with regard to fatal and nonfatal cases.
In summary, the LL genotype of the 5-HT transporter gene promoter polymorphism is associated with a higher risk of MI. Many pathophysiological mechanisms could explain this association and must be explored. These mechanisms are not mutually exclusive and could act in synergy.
Received March 26, 2002; revision received May 7, 2002; accepted May 7, 2002.
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