(Reprinted) JAMA, November 17, 2004—Vol 292, No. 19 2339

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@unipa.it Immunosenescence Unit Department of Pathobiology and Biomedical University of Palermo

Marco Caruso, MD

→ Table. Genotype Distribution and Allele Frequency of +896 A G (Asp299Gly) TLR4 Gene Polymorphisms in Male Patients With Acute Myocardial Infarction, Young Male Controls, and Oldest Old Male Controls From Sicily

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

Abbreviation: AMI, acute myocardial infarction. *The distribution of genotypes was in Hardy-Weinberg equilibrium (by (cid:1)2 test) in all of the groups. †Allele frequencies were significantly different among the 3 groups ((cid:1)2, P(cid:2).001). After adjustment for smoking habits, family history of CVD, and the presence of type 2 dia- betes, obesity, hypertension, hypercholesterolemia, and hypertriglyceridemia, signifi- cant differences in frequencies of single nucleotide polymorphisms persisted be- tweenpatientswithAMIandoldestoldmen(P=.002),andbetweenyoungandoldest old controls (P(cid:2).001).

AccesstoData:DrC.Carusohadfullaccesstoallofthedatainthestudyandtakes 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 Pa- lermo(DrsCandore,Lio,Colonna-Romano,andC.Caruso)andfromtheUniversity ofBologna(DrFranceschi),aswellasfundsfromtheEU5FPT-CIAproject(DrFran- ceschi)andtheItalianMinistryofHealth(GeneticandNon-geneticFactorsofHealth 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 de- sign and conduct of the study; the collection, interpretation, and analysis of the

(P .001), with intermediate values in healthy young con- trols (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 con- Mae?P<. trols and oldest old controls (P .001).

Role of the Sponsors: The organizations funding this study had no role in the de- sign 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

Comment. Some studies have shown that individuals with the Asp299Gly TLR4 SNP have a lower risk of atheroscle- rosis and a decreased risk of acute coronary events inde- pendent of the standard coronary risk factors. However, dis- cordant 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 sub- stantially among the studies.3,5 However, our results sup- port a role of the innate immune defense system and par- ticularly 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 reduc- tion in risk of coronary artery disease in patients carrying the studied SNP.

Disclaimer: Dr Balistreri is a PhD student in the pathobiology PhD curriculum (di- rected by Dr C. Caruso) of Palermo University and this work is in partial fulfill- ment of the requirement for the PhD.

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common gene polymorphisms in cardiovascular diseases and in successful ageing: genetic back- ground of male centenarians is protective against coronary heart disease. J Med Genet.

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Our comparison with the oldest old may help elucidate the role of genetics in age-associated diseases character- ized by a multifactorial etiology. Finally, TLR4 polymor- phisms, which attenuate receptor signaling, enhance the risk of infections5 but decrease that of atherogenesis, pre- sumably 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