Are Endurance Alleles Survival Alleles? Insights from the ACTN3 R577X Polymorphism 

Carmen Fiuza-Luces, Jonatan R. Ruiz, Gabriel Rodriguez-Romo, Catalina Santiago, Felix Gomez-Gallego, Thomas Yvert, Amalia Cano-Nieto, Nuria Garatachea, Maria Moran, and Alejandro Lucia from various institutions in Spain and Sweden conducted a study to investigate whether genetic variants that influence exercise phenotypes could also be associated with exceptional survival. They focused on the Arg(R)577Ter(X) polymorphism (rs1815739) in ACTN3 that encodes the skeletal muscle protein a-actinin-3 since it affects muscle structure/function. The researchers compared the ACTN3 R577X genotype/allele frequencies between centenarians (n=64), young healthy controls (n=283), and two groups of athletes with extreme exercise capacity phenotypes: endurance (50 male professional road cyclists) and power (63 male jumpers/sprinters). 

The results showed no significant differences in genotype/allele frequencies between centenarians (RR:28.8%; RX:47.5%; XX:23.7%), controls (RR:31.8%; RX:49.8%; XX:18.4%), or endurance athletes (RR:28.0%; RX:46%; XX:26.0%). However, there was a significantly higher frequency of the X allele (P=0.019) and XX genotype (P=0.011) in centenarians compared with power athletes (RR:47.6%; RX:36.5%;XX:15.9%). The frequency of the null XX genotype in centenarians was also the highest ever reported in non-athletic Caucasian populations. These findings suggest that a certain survival advantage may be brought about by a-actinin-3 deficiency and the endurance/oxidative muscle phenotype associated with it. 

Citation: Fiuza-Luces C, Ruiz JR, Rodriguez-Romo G, Santiago C, Gomez-Gallego F, et al. (2011) Are Endurance Alleles Survival Alleles? Insights from the R577X Polymorphism. PLoS ONE 6(3): e17558. doi:10.1371/journal.pone.0017558 

Editor: Conrad Earnest, Pennington Biomedical Research Center, United States of America 

Received December 10, 2010; Accepted January 26, 2011; Published March 3, 2011 

Copyright:   2011 Fiuza-Luces et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 

Funding: This study was funded by the Fondo de Investigaciones Sanitarias (FIS, ref. # PS09/00194), and Swedish Council for Working Life and Social (FAS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 

Competing Interests: Alejandro Lucia and Jonatan R. Ruiz are involved with PLoS ONE as Section Editor and Academic Editor, respectively. * E-mail: alejandro.lucia@uem.es . These authors contributed equally to this work. 

Introduction 

Exercise phenotypes have played a crucial role in ensuring human survival over evolution. Some genetic variants that influence exercise phenotypes may be associated with exceptional survival (i.e., reaching 100 years of age). Exercise was essential for survival in Paleolithic societies (e.g., long time tracking persistence for successful hunting), and it would be plausible to speculate that identified genetic variants associated with exercise phenotypes could also be associated with exceptional survival. 

The ACTN3 gene encodes for the synthesis of a-actinin-3 in skeletal-muscle fibers, a sarcomeric protein necessary for producing explosive powerful contractions. A premature stop codon polymorphism [Arg(R)577Ter(X), rs1815739] in ACTN3 affects muscle function and structure. The XX genotype (with a frequency of 18% among European Caucasians) is believed to preclude top-level athletic performance in pure power and sprint sports, especially in women. In contrast, the X allele tends to be overrepresented in humans with an extreme endurance phenotype, i.e., elite endurance athletes. The XX genotype may confer a survival advantage as it is associated with more efficient aerobic metabolism. 

Identifying candidate gene variants associated with longevity assurance is possible by studying the genotype of centenarians. This group of people escaped diseases of the pre-antibiotic era and postponed/avoided several aging-related diseases and their fatal consequences. The researchers compared the allelic and genotypic frequency of the ACTNThe aforementioned criteria were used to randomly select subjects from two universities in Madrid, Spain: Universidad Politecnica (N = 200) and UEM (n = 83). These controls had previously been subjects in research conducted by our group [15,16]. Their maximal oxygen uptake (VO2max) was 48.0 ± 6.4 ml/kg/min. Following recent recommendations [14], genotype results of the ACTN3 R577X polymorphism were replicated in a different laboratory (Progenika Biopharma, Parque Tecnologico de Zamudio, Derio-Vizcaya, Spain) using a newly developed low-density DNA microarray based on allele-specific probes. The design, fabrication, validation, and analysis of the arrays were performed following the procedure described elsewhere [17]. In brief, the PCR products were fluorescently labeled and hybridized to the DNA microarray in an automated platform (Ventana Medical Systems, Inc., Tucson, AZ, USA). The microarrays were scanned (Innopsys S.A., Carbonne, France), and we determined variants using software developed to convert the intensity of the spots into the genotype of each variant.

During 2009-2010, we obtained DNA from saliva samples from 64 centenarians of both genders (57 female, 7 male; aged between 100 and 108 years) living in nursing residencies in the central area of Spain (Meseta Castellana). The most prevalent diseases in the centenarian cohort were osteoarthritis (72%), hypertension (62.5%), dementia (50%), and coronary artery disease (30%). Three centenarians were free of any diagnosed disease.