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Tagging long-lived individuals through vitamin-D receptor (VDR) haplotypes

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Abstract

Longevity is a complex phenomenon involving multiple environmental and biological factors. Genetic studies of longevity have focussed on DNA repair, oxidative damage correction and immune-related genes. Vitamin-D works by modulating mineral homeostasis and key physiological processes such as cell proliferation and immune response. Vitamin-D insufficiency has been largely considered a risk factor for life-limiting illnesses including cardiovascular and immune-related diseases and cancer. Vitamin-D acts through vitamin-D-receptor (VDR), which regulates the expression of vitamin-D-response genes. VDR variants have been associated with susceptibility to cancer, bacterial and viral infections, autoimmune diseases, and allergies. In the present study we evaluated VDR as candidate gene involved in human longevity. We selected five polymorphisms of the VDR gene that capture variability at the 5′, coding and 3′ regions. Genotype data was obtained from 104 octogenarians (>85 years) and 114 controls (17–40 years). Although differences in genotype and allele distribution did not reach statistical significance, haplotype distribution was distinctive, mainly for 3′ region haplotypes and particularly in males. Our results suggest a role for VDR gene variability in aging and longevity.

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References

  • Arai H, Miyamoto KI, Yoshida M et al (2001) The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene. J Bone Miner Res 16:1256–1264

    Article  PubMed  CAS  Google Scholar 

  • Austad SN (2006) Why women live longer than men: sex differences in longevity. Gend Med 3:79–92

    Article  PubMed  Google Scholar 

  • Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    Article  PubMed  CAS  Google Scholar 

  • Bellamy RJ, Hill AV (1998) Host genetic susceptibility to human tuberculosis. Novartis Found Symp 217:3–13

    Article  PubMed  CAS  Google Scholar 

  • Bonafe M, Olivieri F, Cavallone L et al (2001) A gender-dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity. Eur J Immunol 31:2357–2361

    Article  PubMed  CAS  Google Scholar 

  • Capri M, Salvioli S, Monti D et al (2008) Human longevity within an evolutionary perspective: the peculiar paradigm of a post-reproductive genetics. Exp Gerontol 43:53–60

    Article  PubMed  Google Scholar 

  • Chen TC, Chimeh F, Zhiren L et al (2007) Factors that influence the cutaneous synthesis and dietary sources of vitamin D. Arch Biochem Biophys 460:213–217

    Article  PubMed  CAS  Google Scholar 

  • Danescu LG, Levy S, Levy J (2009) Vitamin D and diabetes mellitus. Endocrine 35:11–17

    Article  PubMed  CAS  Google Scholar 

  • de la Torre MS, Torres C, Nieto G et al (2008) Vitamin D receptor gene haplotypes and susceptibility to HIV-1 infection in injection drug users. J Infect Dis 197:405–410

    Article  PubMed  CAS  Google Scholar 

  • Deluca HF, Cantorna MT (2001) Vitamin D: its role and uses in immunology. FASEB J 15:2579–2585

    Article  PubMed  CAS  Google Scholar 

  • Di Bona D, Vasto S, Capurso C et al (2009) Effect of interleukin-6 polymorphisms on human longevity: a systematic review and meta-analysis. Ageing Res Rev 8:36–42

    Article  PubMed  Google Scholar 

  • Dobnig H, Pilz S, Scharnagl H et al (2008) Independent association of low serum 25-hydroxyvitamin d and 1, 25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med 168:1340–1349

    Article  PubMed  CAS  Google Scholar 

  • Fang Y, van Meurs JB, d’Alesio A et al (2005) Promoter and 3′-untranslated-region haplotypes in the vitamin d receptor gene predispose to osteoporotic fracture: the Rotterdam study. Am J Hum Genet 77:807–823

    Article  PubMed  CAS  Google Scholar 

  • Fibla J, Caruz A (2010) Vitamin D and HIV Infection. In: Alfano M (ed) Soluble factors mediating innate immune responses to HIV infection. Bentham eBooks, pp 180–229

  • Franceschi C, Motta L, Valensin S et al (2000) Do men and women follow different trajectories to reach extreme longevity? Italian Multicenter Study on Centenarians (IMUSCE). Aging (Milan) 12:77–84

    CAS  Google Scholar 

  • Garland CF, Gorham ED, Mohr SB, Garland FC (2009) Vitamin D for cancer prevention: global perspective. Ann Epidemiol 19:468–483

    Article  PubMed  Google Scholar 

  • Giacconi R, Cipriano C, Albanese F et al (2004) The -174G/C polymorphism of IL-6 is useful to screen old subjects at risk for atherosclerosis or to reach successful ageing. Exp Gerontol 39:621–628

    Article  PubMed  CAS  Google Scholar 

  • González ER, Benavides FG, Mestre J (1996) La Transición Sanitaria en España desde 1900 a 1990. Rev Esp Salud Pública 70:221–233

    Google Scholar 

  • Gouni-Berthold I, Krone W, Berthold HK (2009) Vitamin D and cardiovascular disease. Curr Vasc Pharmacol 7:414–422

    Article  PubMed  CAS  Google Scholar 

  • Gross C, Eccleshall TR, Malloy PJ et al (1996) The presence of a polymorphism at the translation initiation site of the vitamin D receptor gene is associated with low bone mineral density in postmenopausal Mexican-American women. J Bone Miner Res 11:1850–1855

    Article  PubMed  CAS  Google Scholar 

  • Halsall JA, Osborne JE, Potter L, Pringle JH, Hutchinson PE (2004) A novel polymorphism in the 1A promoter region of the vitamin D receptor is associated with altered susceptibility and prognosis in malignant melanoma. Br J Cancer 91:765–770

    PubMed  CAS  Google Scholar 

  • Hayes DP (2010) Vitamin D and ageing. Biogerontology 11:1–16

    Article  PubMed  CAS  Google Scholar 

  • Heaney RP (2008) Vitamin D in health and disease. Clin J Am Soc Nephrol 3:1535–1541

    Article  PubMed  CAS  Google Scholar 

  • Holick MF (2005) Vitamin D: important for prevention of osteoporosis, cardiovascular heart disease, type 1 diabetes, autoimmune diseases, and some cancers. South Med J 98:1024–1027

    Article  PubMed  Google Scholar 

  • Holick MF (2006) High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 81:353–373

    Article  PubMed  CAS  Google Scholar 

  • Holick MF, Chen TC (2008) Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr 87:1080S–1086S

    PubMed  CAS  Google Scholar 

  • Ingles SA, Ross RK, Yu MC et al (1997) Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. J Natl Cancer Inst 89:166–170

    Article  PubMed  CAS  Google Scholar 

  • Jurutka PW, Remus LS, Whitfield GK et al (2000) The polymorphic N terminus in human vitamin D receptor isoforms influences transcriptional activity by modulating interaction with transcription factor IIB. Mol Endocrinol 14:401–420

    Article  PubMed  CAS  Google Scholar 

  • Keisala T, Minasyan A, Lou Y-R et al (2009) Premature aging in vitamin D receptor mutant mice. J Steroid Biochem Mol Biol 115:91–97

    Article  PubMed  CAS  Google Scholar 

  • Lamberg-Allardt C (2006) Vitamin D in foods and as supplements. Prog Biophys Mol Biol 92:33–38

    Article  PubMed  CAS  Google Scholar 

  • Lanske B, Razzaque MS (2007) Vitamin D and aging: old concepts and new insights. J Nutr Biochem 18:771–777

    Article  PubMed  CAS  Google Scholar 

  • Lash RW, Nicholson JM, Velez L, Van Harrison R, McCort J (2009) Diagnosis and management of osteoporosis. Prim Care 36:181–198

    Google Scholar 

  • Lewontin R (1988) On measures of gametic disequilibrium. Genetics 120:849–852

    PubMed  CAS  Google Scholar 

  • Li N, Stephens M (2003) Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data. Genetics 165:2213–2233

    PubMed  CAS  Google Scholar 

  • Lio D, Scola L, Crivello A et al (2002a) Allele frequencies of +874T→A single nucleotide polymorphism at the first intron of interferon-gamma gene in a group of Italian centenarians. Exp Gerontol 37:315–319

    Article  PubMed  CAS  Google Scholar 

  • Lio D, Scola L, Crivello A et al (2002b) Gender-specific association between -1082 IL-10 promoter polymorphism and longevity. Genes Immun 3:30–33

    Article  PubMed  CAS  Google Scholar 

  • Lips P (2006) Vitamin D physiology. Prog Biophys Mol Biol 92:4–8

    Article  PubMed  CAS  Google Scholar 

  • Morrison NA, Qi JC, Tokita A et al (1994) Prediction of bone density from vitamin D receptor alleles. Nature 367:284–287

    Article  PubMed  CAS  Google Scholar 

  • Nyholt DR (2004) A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 74:765–769

    Article  PubMed  CAS  Google Scholar 

  • Pike JW (1991) Vitamin D3 receptors: structure and function in transcription. Annu Rev Nutr 11:189–216

    Article  PubMed  CAS  Google Scholar 

  • Pilz S, Dobnig H, Nijpels G et al (2009) Vitamin D and mortality in older men and women. Clin Endocrinol (Oxf) 71:666–672

    Article  CAS  Google Scholar 

  • Razzaque MS, Lanske B (2006) Hypervitaminosis D and premature aging: lessons learned from Fgf23 and Klotho mutant mice. Trends Mol Med 12:298–305

    Article  PubMed  CAS  Google Scholar 

  • Roth SM, Zmuda JM, Cauley JA, Shea PR, Ferrell RE (2004) Vitamin D receptor genotype is associated with fat-free mass and sarcopenia in elderly men. J Gerontol A 59:10–15

    Google Scholar 

  • Shroff R, Egerton M, Bridel M et al (2008) A bimodal association of vitamin D levels and vascular disease in children on dialysis. J Am Soc Nephrol 19:1239–1246

    Article  PubMed  CAS  Google Scholar 

  • Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989

    Article  PubMed  CAS  Google Scholar 

  • Sullivan KM, Dean A, Soe MM (2009) OpenEpi: a web-based epidemiologic and statistical calculator for public health. Public Health Rep 124:471–474

    PubMed  Google Scholar 

  • Tuohimaa P (2009) Vitamin D and aging. J Steroid Biochem Mol Biol 114:78–84

    Article  PubMed  CAS  Google Scholar 

  • Tuohimaa P, Tenkanen L, Ahonen M et al (2004) Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries. Int J Cancer 108:104–108

    Article  PubMed  CAS  Google Scholar 

  • Uitterlinden AG, Fang Y, van Meurs JB, Pols HA, van Leeuwen JP (2004a) Genetics and biology of vitamin D receptor polymorphisms. Gene 338:143–156

    Article  PubMed  CAS  Google Scholar 

  • Uitterlinden AG, Fang Y, van Meurs JB, van Leeuwen H, Pols HA (2004b) Vitamin D receptor gene polymorphisms in relation to Vitamin D related disease states. J Steroid Biochem Mol Biol 89–90:187–193

    Article  PubMed  CAS  Google Scholar 

  • Visser M, Deeg DJ, Lips P (2003) Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam. J Clin Endocrinol Metab 88:5766–5772

    Google Scholar 

  • Wall JD, Pritchard JK (2003) Haplotype blocks and linkage disequilibrium in the human genome. Nat Rev Genet 4:587–597

    Article  PubMed  CAS  Google Scholar 

  • Wang TT, Nestel FP, Bourdeau V et al (2004) Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 173:2909–2912

    PubMed  CAS  Google Scholar 

  • Wingard DL (1984) The sex differential in morbidity, mortality, and lifestyle. Annu Rev Public Health 5:433–458

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

ML was 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 Investigación Sanitaria (FIS, PI051778) and Ministerio de Ciéncia e Innovación (CGL 2007-62875). We thank Elaine Lilly, Ph.D. (Writer’s 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.

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Authors and Affiliations

  1. Departament de Ciències Mèdiques Bàsiques, Unitat de Genètica Humana, IRBLleida, Universitat de Lleida, C/Montserrat Roig, 2, 25199, Lleida, Spain

    Marina Laplana, Manuel Sánchez-de-la-Torre & Joan Fibla

  2. Centre de Salut Balàfia-Pardinyes-Secà, Àrea Bàsica de Lleida, Institut Català de la Salut, C/Vidal i Codina, s/n, 25005, Lleida, Spain

    Alicia Aguiló, Ignasi Casado, Miquel Flores & Ramon Sánchez-Pellicer

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  1. Marina Laplana
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  2. Manuel Sánchez-de-la-Torre
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  7. Joan Fibla
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Correspondence to Joan Fibla.

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Laplana, M., Sánchez-de-la-Torre, M., Aguiló, A. et al. Tagging long-lived individuals through vitamin-D receptor (VDR) haplotypes. Biogerontology 11, 437–446 (2010). https://doi.org/10.1007/s10522-010-9273-8

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  • DOI: https://doi.org/10.1007/s10522-010-9273-8

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