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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. 

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

ABSTRACT: 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). We found that the variability at rs1685354 and rs11235972 was associated with HG levels both at a single and haplotypic level in both cohorts. Furthermore, taking advantage of large cohort and period survival data of the oldest cohort, we tested the association of each SNP with survival at 10 years from the baseline visit. Interestingly, we found that allele A at rs11235972, associated in this cohort with lowest HG scores, influences also the survival patterns, with people carrying this allele 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.

Introduction: In 2003, Newman et al. reported that hand grip strength is a useful marker for identifying genes affecting mid- and late-life physical functioning. Twin studies have demonstrated that about 50% of the observed variation in hand grip strength can be explained by genetic effects (Frederiksen et al., 2002). 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, Uncoupling Protein (UCP) genes have been put forward as candidate genes because of their role in energy metabolism. The Uncoupling Protein 3 (UCP3) gene is of particular interest since it 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 polymorphism, 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, On the HG performance might finally result in differential patterns of survival of the different relevant genotypes, we evaluated survival after 10 years from the baseline visit in the 1905 Cohort by using Accelerated Failure Time (AFT) models (Bradburn et al., 2003). Sex, BMI, and the four UCP3 SNPs (one SNP at a time) were considered as covariates. As reported in the paper by Dato et al. (2011), AFT models can be preferred over the more commonly used Cox regression model (Cox, 1972), particularly when, as in the case of the variable sex for the 1905 Cohort, proportional hazard assumptions are not respected (Schoenfeld, 1982, see Supplementary materials). Moreover, with respect to the less intuitive hazard function provided by Cox models, AFT models allow obtaining a clearer explanation of covariate effects by directly linking the estimation of survival time with the values of covariates: a positive regression coefficient indicates that the covariate is associated with higher survival chances; conversely, negative coefficients indicate lower survival chances. In addition, a recent study demonstrated the usefulness of AFT models also in aging research (Swindell, 2009). Then, from the fitted AFT models, sex-adjusted survival curves were obtained, analyzing each SNP independently from each other. Fitting of AFT models was carried out by assuming a Weibull distribution. Subjects alive or immigrated after 10 years from the baseline visit were considered as censored (Gaist et al., 2000).