ScienceDirect Mechanisms of Ageing and Development 128 (2007) 409-411 www.elsevier.com/locate/mechagedev
The Toll-like receptor 4 polymorphism Asp299Gly in longevity and myocardial infarction in German men
a,* Almut Nebel, Friederike Flachsbart, Arne Schafer, Michael Nothnagel, c d a Susanna Nikolaus, Nour Eddine El Mokhtari, Stefan Schreiber
a Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Germany
b Institute of Medical Informatics and Statistics, University Hospital Schleswig-Holstein Kiel,
c Hospital for General Internal Medicine, University Hospital Schleswig-Holstein Kiel, Germany
d Department of Cardiology, University Hospital Schleswig-Holstein Kiel, Germany
Received 7 December 2006; received in revised form 30 March 2007; accepted 3 April 2007 Available online 7 April 2007
Abstract
In a previous study on Sicilian men, an association of the functional polymorphism Asp299Gly in the TLR4 gene was reported with longevity and a reduced risk of myocardial infarction (MI). Here, we sought to confirm the findings in our extensive collection of 273 long-lived men (95-107 years), 606 male early-onset MI patients and 594 appropriate controls from Germany. Despite sufficient statistical power to replicate the findings observed in the South Italians, our results rule out a noteworthy influence of the TLR4 polymorphism upon human longevity or MI in German men. Therefore, the previously described associations in Sicilians might reflect either population-specific or potentially false-positive results. # 2007 Elsevier Ireland Ltd. All rights reserved.
Keywords: Toll-like receptor 4 gene; Longevity; Myocardial infarction; Case-control association; Replication; Reproducibility; Reporting bias
Toll-like receptor 4 (TLR4) is involved in the activation of innate immunity, and TLR4-dependent pro-inflammatory signalling has been implicated in the pathogenesis of atherosclerosis and its clinical manifestations, such as myocardial infarction (MI; Edfeldt et al., 2002). Hence, several studies have investigated the association of the functional single nucleotide polymorphism (SNP) +896 A/G (Asp299Gly) in the TLR4 gene with the risk of MI in Europeans, albeit with conflicting results. In some studies, the minor G allele was shown to be associated with a reduced risk of atherosclerosis and acute coronary events (Kiechl et al., 2002; Ameziane et al., 2003), while in others, it was found to predispose to MI (Edfeldt et al., 2004) or not to be associated at all with the disease (Morange et al., 2004; Zee et al., 2005; Koch et al., 2006).
As MI is a leading cause of death worldwide and is tightly correlated with life expectancy, Asp299Gly has also been tested for association with longevity (Balistreri et al., 2004). In Sicilian men, the G allele was reported as an age-associated marker, being significantly over-represented in 55 long-lived individuals (LLI) compared to 127 younger controls or 105 MI patients, respectively, reflecting a survival advantage for carriers of the SNP (Balistreri et al., 2004).
In this study, DNA samples of 1473 German men drawn from population-based collections were analyzed: 273 LLI (mean age: 97.9 years, range: 95-107 years) and 271 younger controls (mean age: 67.4 years; range 60-75 years; Nebel et al., 2005) as well as 606 MI patients (mean age: 54 years; range: 37-71 years, mean age of disease onset: 48 years; El Mokhtari et al., 2006) and 323 healthy controls (mean age: 62 years; range: 48-77 years; Krawczak et al., 2006) who showed no signs of any cardiac disease. SNP Asp299Gly (rs4986790) was genotyped by a TaqMan SNP Genotyping Assay (Applied Biosystems, Foster City, USA). Logistic regression analysis was performed within the R statistical environment, version 2.3.1 to allow for adjustment of known MI confounding factors.
Our study highlights a common problem of case-control association studies, i.e. the lack of reproducibility. In order to prove the validity of association results, confirmation in independent and larger samples isCambien, F., Juhan-Vague, I., Asp Gly, CD/C-T, plasma levels of the soluble receptor CD and the risk of coronary heart disease: The PRIME Study. Eur. J. Hum., Nebel, A., Croucher, P.J., Stiegeler, R., Nikolaus, S., Krawczak, M., S., No association between microsomal triglyceride transfer (MTP) haplotype and longevity in humans. Proc. Natl. Acad. Sci., R Development Core Team, R: A language and computing. R Foundation for Statistical Computing, Vienna, Austria. www.R-project.org. Zee, R.Y., Hegener, H.H., Gould, J., Ridker, P.M., Toll-like receptor Asp Gly gene polymorphism and risk of atherothrombosis. Stroke, Ioannidis, J.P.A., Molecular bias. Eur. J. Epidemiol., Kiechl, S., Lorenz, E., Reindl, M., Wiedermann, C.J., Oberhollenzer, F., Bonora, E., Willeit, J., Schwartz, D.A., Toll-like receptor polymorphisms and atherogenesis. N. Engl. J. Med., Koch, W., Hoppmann, P., Pfeufer, A., Schomig, A., Kastrati, A., Toll-like receptor gene polymorphisms and myocardial infarction: no association in a Caucasian population. Eur. Heart J..