Association of anxiety-related polymorphisms with sports performance in Chilean long distance triathletes: a pilot study.

Author:Sanhueza, Jorge A.
Position::Research article - Report


The effects of anxiety on athletic performance have been the main target of study in sports psychology recently. Each anxiety disorder has different symptoms, but they cluster around an irrational and excessive fear or dread (Issler et al., 2014). In triathletes, changing situations during training and competition together with the presence of anxiety disorders might cause the maladaptive fatigue syndrome (overtraining syndrome) characterized by: anger, hostility, anxiety, confusion, depression, sadness, lack of energy and apathy, finally resulting in poor performance and/or abandonment of training and competition (Patel et al., 2010). The mental health and athletic performance current model suggests a relationship between psychopathology and athletic performance (Patel et al., 2010). Studies have shown that between 70% to 85% of successful and unsuccessful athletes can be identified using general psychological measures of personality structure and mood, a level above chance, but insufficient for the purpose of athletes selection (Del Coso et al., 2014). Other studies show a deleterious effect of stress and anxiety on athletic performance in various sports (Raglin, 2001).

The biological basis of anxiety disorders focuses on a dysfunctional hypothalamus-pituitary-adrenal (HPA) axis, leading to increased activity and exaggerated response mediated by the neuroendocrine system of cortisol and catecholamines (Drabant et al., 2012). An important modulator is the serotonergic system, controlling HPA axis function on at least two levels: on one hand, activating the corticotropin-releasing factor (CRF) and secondly, by regulating cortisol and CRF activity at the synaptic level (Drabant et al., 2012). In this context, the serotonin transporter (SERT or 5-HTT) regulates serotonin (5-HT) concentrations at the synaptic level (Lee et al., 2004), and more than twelve different traits of human behavior and other systemic diseases have been linked to SERT variations (SLC6A4) (Sysoeva et al., 2009). SLC6A4 repression and the function of important variations in the transcriptional control region (serotonin transporter gene linked polymorphic region; 5-HTTLPR) have been linked to multiple psychopathological conditions, including anxiety disorder (Gonda et al., 2008).

The 5-HTTLPR polymorphism corresponds to a genetic variant in which an insertion-deletion of a 44 base pairs (bp) fragment occurs within SLC6A4, where the shorter variant (deletion, short/short or s/s) results in reduced transcriptional activity and increased vulnerability to affective disorders (Trushkin et al., 2011).

Within the serotonergic system, a crucial study target corresponds to the 5-HT1A receptor, which plays an important role in the self-regulatory function of the central serotonergic system (Noro et al., 2010). Studies evaluating the C(-1019)G polymorphism within this gene show an association with suicide risk, without being associated with depression (Lemonde et al., 2003). Dysfunctions associated with this receptor in knockout 5-HT1A -/ - mice show increased anxious features and stress sensitivity (Lesch, 2001). Animal and cell culture studies demonstrate that increased activity of the HPA axis is associated with decreased expression of the postsynaptic 5-HT1A receptor (Lanfumey et al., 2008).

Another important regulation mechanism of the HPA axis occurs during CRF release and its binding to type 1 and type 2 specific receptors, modulating HPA axis activity (Van Den Eede et al., 2005). Current evidence shows that CRF release regulation is mediated by CRF binding protein (CRF-BP), producing an additional feedback on the HPA axis (Issler et al., 2014). Different studies showed increased expression of CRF-BP in the amygdale, anterior pituitary and portal circulation follo wing increased CRF release (Van Den Eede et al., 2005). Furthermore, CRF-BP knockout mice showed an anxious behavior together with increased CRF concentrations and elevated ACTH and cortisol levels (Van Den Eede et al., 2005).

Corticotropin-releasing factor 2 receptor (CRF2R) is suggested to play a fundamental role in the recovery from stress to calm (Bale et al., 2002). Reports show that CRF2R receptors are required for proper 5-HT1A receptors function in the raphe nuclei, and that they are key for successful stress recovery (Issler et al., 2014).

In addition to its neurotransmitter/modulator in pain perception, substance P (SP) is involved in mood regulation, as demonstrated by its neurokinin-1 receptor (NK1R) antagonists to have antidepressant effects in humans (Noro et al., 2010). In rodents, treatment with NK1R antagonists showed increased 5-HT liberation from the dorsal raphe nucleus (DRN), suggesting local interactions between SP and serotonin in 5-HT1A receptors desensitization, representing a new element in the complex neural circuits proposed for mood regulation (Koller et al., 2006).

Multiple studies have associated angiotensin converting enzyme (ACE) with sports performance, and recently, ACE has been proposed as an important cortisol secretion and HPA axis regulator (Ancelin et al., 2013). The I/I genotype of the ACE rs1799752 polymorphism (I/D) has been associated with reduced plasma levels and tissue activity of ACE, while the D/D genotype was associated with higher plasma concentration and increased cardiac activity of the enzyme together with improved performance in sprint sports (Saber-Ayad et al., 2014). The I allele has been also associated with increased endurance in elite long distance runners, rowers and trail runners (Cam et al., 2005). Moreover, the presence of the D allele increases the ejection fraction and systolic pulmonary artery pressure (Saber-Ayad et al., 2014) together with an increase in CRH and ACTH levels of the HPA axis (Ancelin et al., 2013). In addition, higher ACE plasma levels are associated with lower performance in cycling and jogging in a group of athletes competing in the South Africa Ironman (Domingo et al., 2013).

Based on the background aforementioned, we aimed to explore a possible relationship between the presence of anxiety-related polymorphisms and their association with athletic performance in a group of Chilean long-distance triathletes.



One hundred and ninety two triathlon male competitors (1.9 km swimming, 90 km bike and 21 km of jogging) were evaluated. Clinical assessment consisted in physical measures of body composition by bioelectrical impedance, and a psychiatric interview using the MINI international neuropsychiatric interview, version 5.0, which allows categorizing various Axis I DSM-IV-TR disorders. Anthropometric characteristics are resumed in Table 1.

Every triathlete had experience on the Half Ironman as the entire group ran the same triathlon at least one time. All athletes fulfilled six mesocycles consisting of 3 microcycles each. Different categories were set to establish their performance outcomes. Following the participation of the athletes in the Half Ironman 70.3 competition (Pucon city), overall performance stratification was completed dividing the 192 participants into two opposite performance subgroups, designated as superior performance group (SP, n = 92) and inferior performance group (IP, n = 100), according to times registered in their respective categories. The study was conducted according to the Declaration of Helsinki. All participants accepted to participate by signing an informed consent previously approved by the Research Ethics Committee of Universidad de La Frontera (Protocol number CEC 112/2013).

Blood samples

Venous blood samples were obtained for leukocyte DNA extraction and subsequent polymorphisms genotyping by PCR, PCR-RFLP and qRT-PCR. Genomic DNA was extracted using a protocol previously described by Salazar et al. (Salazar et al., 1998). Afterwards, DNA was quantified by spectrophotometry and diluted to 100 ng/100 [micro]l.


Genotyping of ACE rs1799752 (I/D) and serotonin transporter 5HTT (5-HTTLPR) polymorphisms was completed by conventional PCR, observing for the I/D polymorphism a fragment of 190 bp in the presence of the D allele, and a fragment of 490 bp in the presence of the I allele. For the 5-HTTLPR polymorphism, a fragment of 528 bp was observed for the insertion L/L homozygote genotype, two fragments of 484 bp and 528 bp for the heterozygote S/L, and one 484 bp fragment for deletion genotype S/S.


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