To evaluate differences in VDR variants between young and elderly subjects, indirect data on genotype frequencies of VDR markers have been reported in the literature, but a comparison with our data is inappropriate due to differences in the origin of each population and in selection criteria. We acknowledge that our study has a number of potential limitations. Although octogenarian Caucasian cohorts may have common characteristics, such as the limited medical care available until the 1950s, we cannot exclude potential confounding factors. In particular, two historical events must be taken into account: the Spanish flu epidemic at the beginning of the twentieth century, which depleted the childhood population, and the Civil War (1936-1939) that had an especially important impact on male mortality (Gonzalez et al. 1996). The first event could have produced biological consequences, while the second had a stochastic effect. Another concern refers to the comparison of different birth cohorts, within which we assumed that initial frequencies are similar (Capri et al. 2008). We cannot exclude this confounding factor in our study. However, our cohorts fit Hardy-Weinberg equilibrium in all loci analyzed, and neither disturbances on random matting nor selective factors attributable to the study design were detected.

With respect to the biogerontological significance of the observed association, we can only suggest a correlation. The well-documented impact of vitamin-D levels on the aging process and on age-related diseases is bolstered by our results. In addition, the study results propose a new scenario in which the variability of the VDR gene is also relevant and emphasize the role of VDR genetic background in determining optimal vitamin-D levels for healthy aging.

Acknowledgments: ML was a recipient of a fellowship from the University of Lleida. This work was supported by grants to the University of Lleida (JF, principal investigator) from Fondo de Investigacion Sanitaria (FIS, PI051778) and Ministerio de Ciencia e Innovacion (CGL 2007-62875). We thank Elaine Lilly, Ph.D. (Writers First Aid), for English language revision of the manuscript. We would like to thank the elderly participants and their families who made this study possible.

References:

Arai H, Miyamoto KI, Yoshida M1) "J Gerontol A" should be "J Gerontol A Biol Sci Med Sci"
2) "A bimodal asso- ciation" should be "A bimodal association"
3) "Ope pi" should be "OpenEpi"
4) No errors found
5) "van Leeu- wen" should be "van Leeuwen"; "in vitamin D receptor mutant mice" should be on a new line
6) No errors found
7) "-  -dihydroxyvitamin D" should be "1,25-dihydroxyvitamin D"; there is unnecessary whitespace between the comma and hyphen in "-  ,"
8) No errors found
9) "?  T?A" should be "- 874T>A"; "in a group of Italian centenarians" should be on a new line
10) No errors found
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16) "Clin Endocrinol (Oxf)" should be "Clin Endocrinol (Oxf)."; there is unnecessary whitespace after "(Oxf)"
17) "Fgf" should be "FGF"; there is unnecessary whitespace between the comma and "and" in "FGF  and Klotho mutant mice."
18) No errors found. 

PROCESSED TEXT: 

1: J Gerontol A Biol Sci Med Sci 
2: A bimodal association 
3: OpenEpi 
4: No errors found 
5: van Leeuwen JP 
   in vitamin D receptor mutant mice. J Steroid Biochem Mol Biol 
6: No errors found 
7: 1,25-dihydroxyvitamin D is a direct inducer of antimicrobial peptide gene expression. J Immunol 
8: No errors found 
9: Allele frequencies of -874T>A single nucleotide polymorphism at the first intron of interferon-gamma gene 
   Exp Gerontol 
10: No errors found 
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16: Clin Endocrinol (Oxf). 
17: FGF and Klotho mutant mice. Trends Mol Med 
18: No errors found