 |
|
Role of Toll-like Receptor 4 in Acute Myocardial Infarction and Longevity
To the Editor: A major trait characterizing centenarians is a relatively low frequency of cardiovascular disease (CVD). Since a proinflammatory genotype appears to contribute to the risk of ischemic heart disease, the prevalence of proinflammatory alleles would also be expected to be relatively low in people experiencing longevity.1 Toll-like receptor 4 (TLR4), the activity of which may be modulated by genetic polymorphisms, is a signaling receptor in innate immune defense. It is activated by lipopolysaccharide from gram-negative bacteria and endogenous ligands, including those produced in response to tissue injury. TLR4 is expressed on virtually all cells. However, in atherosclerotic tissue its expression is markedly up-regulated, and the inflammatory mediators produced by its activation exert various atherogenic effects.2-3 In this study, we evaluated whether prevalence of the TLR4 genotype may have an association with acute myocardial infarction (AMI) and with longevity.
Methods. We studied 105 young Sicilian men (mean age, 41 years; range, 20-46 years) consecutively admitted for AMI to the cardiac unit of Palermo University Hospital. Current smoking was present in 74% (former and current in 89%), family history of CVD in 58%, type 2 diabetes in 17%, obesity in 34%, hypertension in 29%, hypercholesterolemia in 61%, and hypertriglyceridemia in 43%.
One control group consisted of 127 Sicilian men matched by age strata (mean age, 38 years; range, 20-50 years). These were students and staff personnel who were judged to be in good health based on their clinical history and on blood tests (complete blood cell count, erythrocyte sedimentation rate, and levels of glucose, blood urea nitrogen, creatinine, electrolytes, C-reactive protein, liver transaminases, iron, proteins, cholesterol, and triglycerides). Of these young controls, 20% were moderate smokers; no other major cardiac risk factor was present.
A second control group consisted of 55 Sicilian oldest old men (mean age, 100 years; range, 96-104 years). By using the demographic lists of the registry offices of Palermo and surrounding municipalities, 166 potentially eligible oldest old men were identified in the Palermo area. Ninety-one (55%) agreed to participate. The control group was composed of the 55 (60%) who did not have any cardiac risk factors or major age-related diseases (eg, coronary heart disease, severe cognitive impairment, severe physical impairment, clinically evident cancer, or renal insufficiency), although some had decreased auditory and visual acuity.4 Because immigration and intermarriage in Sicily have historically been rare, the Sicilian ethnicity of all participants was confirmed by having all 4 grandparents born in Sicily. The study was approved by the hospital ethics committee and written informed consent was obtained from all participants.
DNA was genotyped for the +896 A G (Asp299Gly) TLR4 single-nucleotide polymorphism (SNP) according to published methods.5 The Asp299Gly SNP has been shown to attenuate receptor signaling.3, 5 Differences in SNP frequency among the groups were evaluated by  2 test. We performed a logistic regression analysis to test the association of SNP with AMI after adjustment for smoking habits, family history of CVD, and the presence of type 2 diabetes, obesity, hypertension, hypercholesterolemia, and hypertriglyceridemia. A similar analysis was performed comparing young controls with oldest old controls.
Results. We found significant differences in the frequency of TLR genotypes among the 3 studied groups (P<.001). The Asp299Gly SNP was underrepresented in patients with AMI and overrepresented in the oldest old men (P<.001), with intermediate values in healthy young controls (Table). After adjustment for risk factors, significant differences in SNP frequency persisted between patients with AMI and oldest old men (P = .002) and between young controls and oldest old controls (P<.001).
|
|
|
|
Table. Genotype Distribution and Allele Frequency of +896 AG (Asp299Gly) TLR4 Gene Polymorphisms in Male Patients With Acute Myocardial Infarction, Young Male Controls, and Oldest Old Male Controls From Sicily
|
|
|
Comment. Some studies have shown that individuals with the Asp299Gly TLR4 SNP have a lower risk of atherosclerosis and a decreased risk of acute coronary events independent of the standard coronary risk factors. However, discordant results have been reported. The causes of the discrepancies are not clear, but the inclusion criteria, the study populations, and the measured end point differed substantially among the studies.3, 5 However, our results support a role of the innate immune defense system and particularly TLR4 in CVD. These results fit well with a recent study supporting a role of TLR4 in atherogenesis3 and with the largest epidemiologic evaluation so far,6 which showed lower levels of C-reactive protein with concomitant reduction in risk of coronary artery disease in patients carrying the studied SNP.
Our comparison with the oldest old may help elucidate the role of genetics in age-associated diseases characterized by a multifactorial etiology. Finally, TLR4 polymorphisms, which attenuate receptor signaling, enhance the risk of infections5 but decrease that of atherogenesis, presumably by limiting inflammatory responses. Hence, the mutation might result in an increased chance of longevity in a modern environment with reduced pathogen load and improved control of severe infections by antibiotics.1
Access to Data: Dr C. Caruso had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analyses.
Funding/Support: This study was supported by grants from the University of Palermo (Drs Candore, Lio, Colonna-Romano, and C. Caruso) and from the University of Bologna (Dr Franceschi), as well as funds from the EU 5FP T-CIA project (Dr Franceschi) and the Italian Ministry of Health (Genetic and Non-genetic Factors of Health in Elderly) (Drs Franceschi and Colonna-Romano). The collaboration between the "Gruppo di Studio sull'Immunosenescenza" coordinated by Dr C. Caruso and the Istituto Nazionale di Riposo e Cura per Anziani (INRCA), Ancona, was supported by an INRCA grant (Longevity and Elderly Disability Biological Markers).
Role of the Sponsors: The organizations funding this study had no role in the design and conduct of the study; the collection, interpretation, and analysis of the data; the preparation of the data; or the preparation, review, or approval of the manuscript.
Disclaimer: Dr Balistreri is a PhD student in the pathobiology PhD curriculum (directed by Dr C. Caruso) of Palermo University and this work is in partial fulfillment of the requirement for the PhD.
Carmela Rita Balistreri, SciD;
Giuseppina Candore, PhD;
Giuseppina Colonna-Romano, SciD;
Domenico Lio, MD
Immunosenescence Unit
Department of Pathobiology and Biomedical Methodologies
University of Palermo
Palermo, Italy
Marco Caruso, MD;
Enrico Hoffmann, MD
Department of Internal Medicine
Cardiovascular and Nephro-Urological Diseases
University of Palermo
Claudio Franceschi, MD
Italian National Research Center on Aging
Ancona, Italy
Department of Experimental Pathology and Interdepartmental Center "L. Galvani"
University of Bologna
Bologna, Italy
Calogero Caruso, MD
marcoc{at}unipa.it
Immunosenescence Unit
Department of Pathobiology and Biomedical Methodologies
University of Palermo
1. Lio D, Candore G, Crivello A, et al. Opposite effects of IL-10 common gene polymorphisms in cardiovascular diseases and in successful ageing: genetic background of male centenarians is protective against coronary heart disease. J Med Genet. 2004;41:790-794.
FREE FULL TEXT
2. Michelsen KS, Wong MH, Shah PK, et al. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc Natl Acad Sci U S A. 2004;101:10679-10684.
FREE FULL TEXT
3. Edfeldt K, Bennet AM, Eriksson P, et al. Association of hypo-responsive toll-like receptor 4 variants with risk of myocardial infarction. Eur Heart J. 2004;25:1447-1453.
FREE FULL TEXT
4. Franceschi C, Motta L, Valensin S, et al. Do men and women follow different trajectories to reach extreme longevity? Italian Multicenter Study on Centenarians (IMUSCE). Aging (Milano). 2000;12:77-84.
PUBMED
5. Kiechl S, Lorenz E, Reindl M, et al. Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med. 2002;347:185-192.
FREE FULL TEXT
6. Kolek MJ, Anderson JL, Muhlestein JB, et al. Toll-like receptor 4 D299G polymorphism predicts lower risk of coronary artery diseases and diabetes [abstract]. Circulation. 2003:108S.
Letters Section Editor: Robert M. Golub, MD, Senior Editor.
JAMA. 2004;292:2339-2340.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Genetic Epidemiology in Aging Research
Fallin and Matteini
J Gerontol A Biol Sci Med Sci 2009;0:gln021v1-gln021.
ABSTRACT
| FULL TEXT
Prevalence in the United States of Selected Candidate Gene Variants: Third National Health and Nutrition Examination Survey, 1991-1994
Chang et al.
Am J Epidemiol 2009;169:54-66.
ABSTRACT
| FULL TEXT
Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart
Chao
Am. J. Physiol. Heart Circ. Physiol. 2009;296:H1-H12.
ABSTRACT
| FULL TEXT
A Genetic-Demographic Approach Reveals Male-Specific Association Between Survival and Tumor Necrosis Factor (A/G)-308 Polymorphism
Cardelli et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2008;63:454-460.
ABSTRACT
| FULL TEXT
Review: Variability of host pathogen interaction
Hermann
Innate Immunity 2007;13:199-218.
ABSTRACT
Toll-like receptor 4 polymorphisms and idiopathic chromosomally normal miscarriage
Hirschfeld et al.
Hum Reprod 2007;22:440-443.
ABSTRACT
| FULL TEXT
Toll-like receptor 4 gene polymorphisms and myocardial infarction: no association in a Caucasian population
Koch et al.
Eur Heart J 2006;27:2524-2529.
ABSTRACT
| FULL TEXT
Role of the pyrin M694V (A2080G) allele in acute myocardial infarction and longevity: a study in the Sicilian population
Grimaldi et al.
J. Leukoc. Biol. 2006;79:611-615.
ABSTRACT
| FULL TEXT
|
