The OR values were adjusted for sex and age. Significant P-values are in italic CAD coronary artery disease, CI confidence intervals, OR odds ratio, SNP single nucleotide polymorphism

in this population segment. In contrast, the major strengths of our study were the clear definition that we used for the criterion of exceptional longevity (with all “ ” cases being centenarians or semi-supercentenarians ) and the fact that the analyses were performed in two totally independent cohorts from both ethnic and geographic perspectives.

There is evidence indicating an association, especially in Caucasian cohorts, of the rs1333049 SNP we studied here and risk of CAD (Wellcome Trust Case Control Consortium 2007; Angelakopoulou et al. 2012; Bressler et al. 2010; Dandona et al. 2010; Ellis et al. 2010; Karvanen et al. 2009; McPherson 2010; Mendonca ’ et al. 2011; Muendlein et al. 2009; O Donnell et al. 2011; Palomaki et al. 2010; Plichart et al. 2012; Samani et al. 2009; Samani et al. 2007; Schunkert et al. 2008) and ’ vascular dementia (besides Alzheimer s disease) (Emanuele et al. 2011), with the C-allele exerting an unfavorable effect. The rs1333049 SNP has been linked with CAD-related phenotypes in non-Caucasian cohorts, and especially with myocardial infarction in Japanese people, with a frequency of the risk C-allele of 52.8 % in 589 individuals who had suffered myocardial infarction (Hiura et al. 2008). Further, the C-allele was recently associated with excess mortality independent ≥ of CAD risk factors in old ( 71 years) individuals (Dutta et al. 2011).

In summary, our data overall replicate and extend the original data by Emanuele et al. (2010) in that they suggest that the rs1333049 (G/C) polymorphism in chromosome 9p21.3 polymorphism could be among the numerous variants exerting a certain contribution to exceptional longevity in Mediterranean (Southern European) cohorts. However, such association was not replicated in the healthy Japanese population and further corroboration is needed in other ethnic/geographic groups worldwide.

Acknowledgments This study was funded by the Fondo de Investigaciones Sanitarias (FIS, refs. # PI12/00914, PI10/00036, and PI12/00788) and was supported in part by grants from the program “A Grant-in-Aid for Challenging Exploratory Research” (24650414 to N. Fuku) from the Ministry of Education, Culture, Sports, Science and Technology and by a Grant-in-Aid for Scientific Research from the Ministry of Health, Labor, and Welfare of Japan (to M. Miyachi).

genotype distribution of Spanish centenarians vs. their healthy (CAD-free) controls suggests that the potential influence of the rs1333049 SNP on exceptional longevity goes beyond its documented influence on CAD. With regards to this, although the functional significance of the rs1333049 SNP remains to be clearly elucidated, and the 9p21.3 locus does not contain any known expressed gene products, it lies CDKN2A CDKN2B adjacent to and , two important cell cycle regulators. Both are cyclin-dependent kinase inhibitor genes, which regulate the G1 phase of the cell cycle by inhibition of cyclin/cyclin-dependent kinases, which raises the possibility that rs1333049 may modulate the rate of cellular aging (Emanuele et al. 2010). In fact, recent genomewide scanning has CDKN2A CDKN2B suggested an association between / and extreme longevity, and CDKN2A performs a key step in the p53 pathway, the latter playing a crucial role in inducing cellular senescence (Sebastiani et al. 2012).

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