(R Development Core Team, 2006). The study was approved by the Ethics Committee of the University Hospital Schleswig- Holstein in Kiel.

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 is mandatory. This requirement is even more important for findings that are derived from underpowered studies where the sizes of the samples and of the predicted effects are small (as in Balistreri et al., 2004). In such a setting, the generated research claims are likely to suffer from type-1 errors. Another problem (e.g. for meta-analysis) is a reporting bias, with negative or ‘‘null’’ results having a publication disadvantage over positive ones. Correcting past false claims is as important as producing new scientific discoveries (Ioannidis, 2005). But often research papers that refute a previous finding are declined by the journal that printed the original article. In order to minimize the problem of selective reporting, a procedure which ensures that null results and refutations are published should be adopted by journals, as already proposed by Ioannidis (2006). This practice would provide a more accurate and balanced view of all the obtained research evidence.

Assuming a G allele frequency of 0.059 in the controls and allelic odds ratio characteristics of the Sicilian samples (Balistreri et al., 2004), our study would have had a power of (cid:2)80% to replicate the reported findings. However, in our collections, there was no evidence for an association between Asp299Gly and either longevity or MI (the latter comparison was performed after adjustment for the five major cardiac risk factors; Table 1). Also the comparison of the LLI, who had no clinically relevant atherosclerosis in their lives, with the MI patients revealed no significant association (Table 1).

In a previous study on Sicilian men, Asp299Gly (+896 A ! G) was reported to be associated with longevity. A statistically significant increase in the frequency of the minor G allele was observed in 55 LLI (14.6%) compared to 127 younger controls (5.9%) and to 105 MI patients (2.4%), respectively, indicating a survival advantage and a decreased risk of MI for carriers of the SNP (Balistreri et al., 2004). This finding is consistent with those reported by Kiechl et al. (2002), who initially described the association of the Asp299Gly polymorphism with a decreased risk of carotid and femoral artery atherosclerosis, and by Ameziane et al. (2003) showing association with a reduced risk of coronary syndrome. However, data from our extensive samples suggest that this polymorphism exhibits no significant influence on the ability of attaining exceptional old age and is not associated with a reduced risk of MI in German men (Table 1). In particular, there is no trend towards a lower G frequency in German MI patients, as suggested by the South Italian samples. Our finding is in very good agreement with several investigations, including a recent large-scale study that also observed a lack of association between Asp299Gly and MI in 2772 male German patients (Morange et al., 2004; Zee et al., 2005; Koch et al., 2006). Therefore, the previously reported associations in Sicilians might reflect either population-specific or potentially false- positive results; the latter could be caused by the very small sample sizes examined (Balistreri et al., 2004) in combination with the low frequency of the studied SNP. To demonstrate a population-specific association of this polymorphism with longevity or MI, replications with more extensive DNA collectives of Sicilian origin will be necessary.

Acknowledgements

This study was supported by the German Federal Ministry of Science and Education (BMBF) through (i) an Explorative Project (0313359) of the National Genome Research Network (NGFN-2) to S.S. and (ii) a grant to M.N. (0313437A). The funding sources had no influence on the study or the report of the results. The manuscript was submitted first to JAMA on 09- 11-2006 and subsequently submitted to Mechanisms of Ageing and Development on 07-12-2006.

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