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Mechanisms of Ageing and Development

journal homepage: www.elsevier.com/locate/mechagedev

UCP3 polymorphisms, hand grip performance and survival at old age: Association analysis in two Danish middle aged and elderly cohorts

Serena Dato a,b,*, Mette Soerensen b,c,d, Alberto Montesanto a, Vincenzo Lagani e, Giuseppe Passarino a, Kaare Christensen b,c,d, Lene Christiansen b,c,d

aDepartment of Cell Biology, University of Calabria, Ponte Pietro Bucci cubo 4C, 87036 Rende (CS), Italy bThe Danish Aging Research Center, Epidemiology, Institute of Public Health, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000 Odense C, cDepartment of Clinical Genetics, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark dDepartment of Clinical Biochemistry and Pharmacology, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark eBio Informatics Laboratory, Institute of Computer Science, Foundation for Research and Technology (Hellas), Heraklion, Greece

A B S T R A C T

An efficient uncoupling process is generally considered to have a protective effect on the aging muscle by slowing down its age-related decay. Genetic polymorphisms in the Uncoupling Protein 3 (UCP3) gene, whose product is mainly expressed in skeletal muscle, were suggested to be associated with hand grip (HG) performances in elderly populations. Considering the population specificity of the quality of aging, we aimed to add further support to this evidence by analyzing the association between four SNPs in the UCP3 gene and relative haplotypes in two large cohorts of middle aged (N = 708) and oldest old Danes (N = 908).Wefoundthatthevariabilityatrs1685354andrs11235972wasassociatedwithHGlevelsboth at single and haplotypic level in both cohorts. Furthermore, taking advantage of large cohort and period survival data ofthe oldest cohort,wetestedthe association ofeach SNPwith survival at10 years from the baseline visit. Interestingly, we found that allele A at rs11235972, associated in this cohort with lowest HG scores,influences also the survivalpatterns, with people carryingthisallele showing higher mortality rates. On the whole, our work supports the role of UCP3 gene in functional status and survival at old age. or 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

2003; Newman et al., 2006). Furthermore, twin studies demon- strated that about 50% of the observed variation in hand grip strength can be explained by genetic effects (Frederiksen et al., 2002), thus pointing out this phenotype as a useful marker for the identification of genes affecting mid- and late-life physical functioning. Several associations have been reported between hand grip and the variability of genes involved in inflammatory response, myostatin signaling, neuron and bone metabolism (Roth et al., 2001; Arking et al., 2006; De Mars et al., 2007; Walsh et al., 2009; Dato et al., 2010; Windelinckx et al., 2011). Recently the Uncoupling Protein (UCP) genes have been put forward as candidate genes, because of their role in energy metabolism. Of particular interest is the Uncoupling Protein 3 (UCP3) gene, since this is expressed in skeletal muscle where it regulates fatty acid metabolism, oxidative status, and Reactive Oxygen Species (ROS) production. A previous report showed that a functional polymor- phism, located in the promoter region of the UCP3 gene (rs1800849), significantly affects hand grip strength in an elderly population from southern Italy (Crocco et al., 2011), suggesting a correlation between the uncoupling process and the regulation of muscle metabolism/catabolism in the elderly.

The reduction of muscle mass in the elderly, known as sarcopenia, becomes so significant after the fifth decade of life that it is widely studied as one of the most important markers of human aging. Furthermore, sarcopenia is regarded as one of the major contributors to frailty (Morley et al., 2001), considering that the loss of muscle mass influences metabolic adaptation, immunological response to disease, capability to respond to environmental stress (Schrager et al., 2003) and so has a relevant impact on the overall homeostasis at old age. Operatively, sarcopenia is measured through the reduction of hand grip strength, which is considered a measure of the overall skeletal muscle mass, observed to gradually and significantly decrease as the individual ages (Doherty, 2003). Hand grip strength is generally considered a very reliable marker of the functional status, as well as one of the most effective predictors of disability and mortality in

* Corresponding author at: Department of Cell Biology, University of Calabria, 87036 Rende, Italy. Tel.: +39 0984 492933; fax: +39 0984 492911. E-mail address: s.dato@unical.it (S. Dato).

0047-6374/$ – see front matter © 2 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mad.2012.06.004

In addition, recent evidences report as the genetic variability of UCP2, UCP3 and UCP4 affects the individual’s chances of surviving up to a very old age in the same population, thus confirming the relevance of the uncoupling pathway as candidate for human longevity (Rose et al., 2011a, 2011b).

For each UCP3 polymorphism, allele frequencies were estimated by gene countingfromtheobservedgenotypes.Hardy–Weinbergequilibriumwastestedby aMonte-Carloapproach basedon10,000randomallele permutations(Weir,1996). Standard errors for alleles were computed according to the hypothesis of the multinomial distribution.