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

Marina Laplana • Manuel Sa´nchez-de-la-Torre • Alicia Aguilo´ • Ignasi Casado • Miquel Flores • Ramon Sa´nchez-Pellicer • Joan Fibla

Received: 31 January 2010/Accepted: 6 April 2010/Published online: 21 April 2010  Springer Science+Business Media B.V. 2010

in genotype and allele distribution did not reach statistical significance, haplotype distribution was distinctive, mainly for 30 region haplotypes and particularly in males. Our results suggest a role for VDR gene variability in aging and longevity.

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 modu- lating 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 dis- eases 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 vari- ability at the 50, coding and 30 regions. Genotype data was obtained from 104 octogenarians ([85 years) and 114 controls (17–40 years). Although differences

Introduction

Longevity is a complex phenomenon in which environmental, social, stochastic and biological fac- tors are involved. Maximum lifespan potential of individuals has a strong biological component; pop- ulation life expectancy is a multifactorial trait based on both biological and non-biological factors. In humans, as in other species, long-lived individuals emerge as a result of a successful life, lack of stochastic damaging factors and healthy aging. Recent socioeconomic improvements and advances in prevention and treatment of diseases have reduced infant mortality as well as allowing individuals to survive to extreme old age. As a result, life expec- tancy in humans has increased in developed coun- tries, with no effect on maximum lifespan potential. Social and technological improvements have been crucial to increased human longevity, creating a new scenario in which longevity-related biological factors

M. Laplana   M. Sa´nchez-de-la-Torre   J. Fibla (&) Departament de Cie`ncies Me`diques Ba`siques, Unitat de Gene`tica Humana, IRBLleida, Universitat de Lleida, C/Montserrat Roig,

,

Lleida, Spain e-mail: joan.fibla@cmb.udl.cat

A. Aguilo´   I. Casado   M. Flores   R. Sa´nchez-Pellicer Centre de Salut Bala`fia-Pardinyes-Seca`, A` rea Ba`sica de Lleida, Institut Catala` de la Salut, C/Vidal i Codina, s/n, 25005 Lleida, Spain

Several VDR polymorphisms with functional have been described in the promoter, coding 30 untranslated region (UTR) (Uitterlinden et al. Two common polymorphisms, Cdx (rs1568820) A1012G (rs4516035), have been located in the regulatory region that affect binding to transcription The rs1568820 polymorphism is a G to A between exons 1f and 1e that alters the site for the intestinal-specific transcription ‘‘caudal-related homeodomain protein-2’’ (Cdx- affecting vitamin-D-VDR-mediated intestinal cal- absorption (Arai et al. 2001). The rs4516035 is an A to G transition located between and 1a exons that modifies the GATA-3 transcrip- factor recognition sequence, involved in the of Th2 polarization (Halsall et al. 2004). addition, a common FokI (rs10735810) polymor- has been described in the VDR coding region alters the first ATG start site to an alternate ACG giving rise to a VDR protein that is three acids shorter (424 aas versus 427 aas) (Gross al. 1996). Functional differences among rs10735810 shows that VDR protein coded by the allele (short 424 aas) interacted more effi- with TFIIB and showed greater transcriptional than the full-length VDR protein coded by allele (Jurutka et al. 2000). Finally, a common fragment length polymorphism (RFLP), as BsmI (rs1544410), and a microsatellite designated as PolyA (rs17878969), has described in the 30-UTR region (Morrison et al. Ingles et al. 1997). Functional effects of 30-UTR have been related to alterations in VDR mRNA (Fang et al. 2005).

have been able to operate. The aging process has been considered the result of the accumulation of damages in cells and tissues that, left uncorrected, produces a systemic dysfunction concluding in death. Through- out the lifespan, however, cell maintenance mecha- nisms, such as DNA-repairing enzymes, correction of oxidative damage and immune system response against pathogens and tumour cells, attempt to correct the damage.

status, vitamin-D has been largely considered pro- tective and a promoter of good health (Holick and Chen 2008). Pleiotropic effects of vitamin-D have been largely known to affect mineral metabolism, cell proliferation and immune response modulation. Vita- min-D status has been described as involved in life- limiting diseases (Heaney 2008) such as cancer (Garland et al. 2009), cardiovascular diseases (Gouni-Berthold et al. 2009), osteoporosis (Lash et al. 2009), sarcopenia (Roth et al. 2004; Visser et al. 2003) and diabetes (Danescu et al. 2009). In addition, vitamin-D has an important role in the modulation of the immune response, inducing micro- bicide factors against bacterial infections (Wang et al. 2004) and controlling the exacerbation of the cellular immune response (Deluca and Cantorna 2001). Based on this, it has been proposed a major positive role for vitamin-D in biogerontology by reducing suscepti- bility in the elderly to chronic degenerative diseases (Hayes 2010).