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Association study of performance-related polymorphisms in Brazilian 1 
combat-sport athletes highlights variants in the GABPB1 gene 2 
 3 
João Paulo L. F. Guilherme,1 Tácito P. Souza-Junior,2 and Antonio H. Lancha Junior1 4 
 5 
1Laboratory of Applied Nutrition and Metabolism, School of Physical Education and Sport, University of 6 
São Paulo, São Paulo, Brazil; 2Research Group on Metabolism, Nutrition and Strength Training, 7 
Department of Physical Education, Federal University of Parana, Curitiba, Brazil 8 
 9 
ABSTRACT 10 
Combat sports have an intermittent nature, with mixed anaerobic and aerobic energy 11 
production. Here, we investigated whether polymorphisms that have been previously suggested 12 
as genetic markers for endurance or power phenotypes were associated with combat-sport 13 
athletic status. A total of 23 previously reported performance-related polymorphisms were 14 
examined in a Brazilian cohort of 1,129 individuals (164 combat-sport athletes and 965 15 
controls), using a case-control association study. We found that the GABPβ1 gene (also known 16 
as NRF2) was associated with athletic status, with the minor G (rs7181866) and T (rs8031031) 17 
alleles overrepresented in athletes (P ≤ 0.003), especially among world-class competitors (P ≤ 18 
0.0002). These findings indicate that single nucleotide polymorphisms (SNPs) within the 19 
GABPβ1 gene increase the likelihood of an individual being a combat-sport athlete, possibly due 20 
to a better mitochondrial response to intermittent exercises. 21 
 22 
Athletic Status; Genetics; Intermittent exercise; Mitochondrial function; Nuclear Respiratory 23 
Factor 2 24 
 25 
BACKGROUND/MOTIVATION FOR THE STUDY 26 
The current scientific literature indicates a complex relationship between our genome and 27 
environmental factors in determining elite athletic performance, and an ongoing effort to 28 
discover genetic variants underlying top-level performance has been performed across diverse 29 
populations (3). In this regard, most genetic studies categorize athletes into two opposite groups 30 
based on the predominant metabolic demand imposed by training or competition (anaerobic- or 31 
aerobic-orientated athletes). Due to the anaerobic demand required by combat sports, these 32 
athletes are usually classified as anaerobic (power) athletes (3). However, genetic associations 33 
found in power athletes are not always confirmed in combat-sport athletes. It should be noted 34 
that combat sports also present a relevant contribution of the aerobic metabolism. Although the 35 
anaerobic component is important for success in combat sports, greater aerobic fitness results 36 
in faster recovery between intense efforts (5). Thus, they have a mixed metabolic profile, which 37 
may have unique genetic associations. Combat sports can be classified as a striking contest 38 
(the competitors strike each other with their limbs to score points), a grappling contest (the 39 
competitors attempt to control each other’s movements to achieve a dominant position on the 40 
ground) or a combined contest (competitors use a combination of striking and grappling 41 
techniques). There are differences between these combat sports contests, but a common 42 
element is their intermittent nature (1), which, compared to power- or endurance-oriented 43 
sports, has been less studied. Therefore, this study aimed to explore the association of 44 
performance-related polymorphisms in Brazilian combat-sport athletes. 45 
 46 
PHENOTYPE 47 
The study was designed to assess athletic status using a case-control approach. Selected 48 
polymorphisms were compared between combat-sport athletes (the cases) and non-athlete 49 
individuals (the controls). To be classified as an athlete, the individual was required to be 50 
associated with an official sports federation and regularly participate in their official 51 
competitions. To ensure that the recruited athletes were representative of the best Brazilian 52 
competitors, current and former Brazilian national team members were invited to participate in 53 
the study. On the other hand, to be classified as a non-athlete, the individual was required to 54 
never have been associated in any sports federation. These individuals are representatives of 55 
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the general Brazilian population. The study was approved by the Research Ethics Committee of 56 
the School of Physical Education and Sport, University of São Paulo. Informed consent was 57 
obtained from each participant. 58 
Cohort Details. The study cohort was composed of 1,129 Brazilians stratified into two groups. 59 
The combat-sport group comprised 164 athletes (125 men and 39 women; mean age ± SD = 60 
29.4 ± 10.3 years), of which 107 were from grappling combat sports (Judo, Jiu-Jitsu and 61 
Wrestling), 47 were from striking combat sports (Karate, Taekwondo, Muay Thai, Kung-Fu and 62 
Fencing), and 10 were from combined combat sports (Mixed Martial Arts). Of all the athletes 63 
evaluated, 88 (54%) have successfully represented Brazil in world-class competitions in recent 64 
years. The control group comprised 965 healthy non-athletic individuals (562 men and 403 65 
women; mean age ± SD = 35.1 ± 17.6 years) from the same places of origin of athletes. 66 
Type of study. Candidate SNP(s). 67 
Details of the SNP(s) studied. A total of 23 polymorphisms in 20 genes were included in the 68 
study (see Supplemental Table for complete list), all of which had been associated with power or 69 
endurance phenotypes in at least one other study. Genomic DNA was isolated from buccal 70 
epithelial cells, and sample quality assessment was performed by spectrophotometry 71 
(NanoDrop 2000, Thermo Scientific, Waltham, MA, USA). SNPs were determined via real-time 72 
polymerase chain reaction (PCR) using pre-designed and specific TaqMan SNP Genotyping 73 
Assays (Applied Biosystems, Foster City, CA, USA), performed on a QuantStudio Real-Time PCR 74 
system (Applied Biosystems). The only analyzed variant that was not a SNP was the ACE 75 
insertion/deletion polymorphism, which was genotyped using PCR and melting curve analysis, 76 
performed on a Rotor-Gene Q Real-Time PCR cycler (Qiagen, Hilden, Germany). Athlete and non-77 
athlete samples were analysed together and distributed randomly on the PCR plates. 78 
Analysis model. The Chi-square test was used to test for the presence of the Hardy-Weinberg 79 
equilibrium (HWE) in our control groups, and to compare allele frequencies between athletes 80 
and non-athletes. For the associated polymorphisms, an additional analysis was carried out 81 
between world-class competitors and non-athletes. It was expected that the association 82 
becomes stronger when considering only the most competitive athletes. The significance level 83 
was established at P 0.05), and the respective allelic frequencies are 89 
described in the Supplemental Table. An association was identified between athletic status and 90 
SNPs within the GA-binding protein transcription factor subunit beta 1 (GABPβ1) gene. For both 91 
rs7181866 and rs8031031, the effect allele was overrepresented in combat-sport athletes, 92 
especially in world-class competitors. The G-allele in rs7181866 was found in 4% of the non-93 
athlete group compared to 8% of the combat-sport group (P = 0.003) or 10.9% of world-class 94 
competitors (P = 0.0002). The T-allele in rs8031031 was found in 4% of the non-athlete group 95 
compared to 9.5% of the combat-sport group (P = 0.002) or 11.9% of world-class competitors (P 96 
significant even after FDR correction. It is worth noting 97 
that these two SNPs are in high linkage disequilibrium (D' = 0.99, r2 = 0.97). 98 
 99 
INTERPRETATION 100 
SNPs within the GABPβ1 gene (a master regulator of mitochondrial function) increase the 101 
likelihood of an individual being a combat-sport athlete. GA-binding protein (also known as 102 
nuclear respiratory factor or NRF2) is a complex protein, consisting of alpha and beta subunits 103 
(encoded by separate genes). Deacetylation of GABPβ1 facilitates complex formation with 104 
GABPα and its transcriptional activation, promoting proper mitochondrial function (4). High-105 
intensity interval training has been used effectively to improve aerobic fitness of combat-sport 106 
athletes (5), and given the ability of this training to increase mitochondrial capacity (2), it is not 107 
surprising that gene variants associated with mitochondrial function are overrepresented in 108 
combat-sport athletes. It seems plausible to assume that combat-sport athletes may be more 109 
responsive to intermittent efforts and therefore, their classification as power athletes should be 110 
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used with caution. SNPs within the GABPβ1 gene may be contributing to a greater innate 111 
predisposition to intermittent efforts. 112 
 113 
ACKNOWLEDGMENTS 114 
The authors are grateful to all participants who kindly provided their samples for DNA 115 
analysis and to Professor Alexandre da Costa Pereira from Laboratory of Genetics and Molecular 116 
Cardiology – University of Sao Paulo for access to the QuantStudio Real-Time PCR system. 117 
 118 
GRANTS 119 
This study was supported by grant from the São Paulo Research Foundation (FAPESP; grant 120 
#2012/22516-6). 121 
 122 
DISCLOSURES 123 
No conflicts of interest, financial or otherwise, are declared by the authors. 124 
 125 
AUTHOR CONTRIBUTIONS 126 
J.P.L.F.G. and A.H.L.J. conceived and designed research; J.P.L.F.G. performed experiments 127 
and analyzed data; J.P.L.F.G. and T.P.S.J. interpreted results of experiments; J.P.L.F.G. drafted 128 
manuscript; T.P.S.J and A.H.L.J. edited and revised manuscript. J.P.L.F.G., T.P.S.J. and A.H.L.J. 129 
read and approved final version of manuscript. 130 
 131 
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Supplemental material available at 151 
(https://figshare.com/s/547bcbb4447d0db724ca) 152 
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Appendix: The rationale and criteria for SNPs selection. 164 
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This study was part of a larger research project, which aimed to identify the polygenic 166 
profile of Brazilian elite athletes (18). SNPs were selected based on the relevance 167 
and consistency of associations previously described in the scientific literature until 168 
January 2015. 169 
 170 
First, the selection of polymorphisms to be used was based on the list of 171 
polymorphisms used in the first studies that assessed the polygenic profile of 172 
endurance (8, 31) or power (30) athletes, accounting 15 polymorphisms in 13 genes 173 
(rs17602729, rs699, rs1805086, rs8192678, rs2016520, rs2070744, rs1815739, 174 
rs8031031, rs7181866, rs12594956, rs1799752, NcoI RFLP 1170 bp/985+185 bp at 175 
19q13.2-q13.3, rs1799945, rs1800795 and rs4253778). However, 3 polymorphisms 176 
from these initial studies (NcoI RFLP 1170 bp/985+185 bp at 19q13.2-q13.3, 177 
rs1799945 and rs1800795) were not included due to a lack of replication at that time 178 
(January 2015). Moreover, rs4253778 did not meet the Hardy-Weinberg equilibrium 179 
in our sample and therefore was also not included in the present study. 180 
 181 
Second, an electronic search of the scientific literature (using the PubMed, 182 
SPORTDiscus and Web of Science databases) was undertaken to identify other 183 
candidate polymorphisms, that is, SNPs associated with human physical 184 
performance in populations other than the Brazilian. The following search terms were 185 
used: “genetics”, “polymorphisms”, “athletes”, “endurance”, “power”, and 186 
“performance”. SNPs were selected based on the degree of association and sample 187 
size (statistical power). In this step, a total of 12 polymorphisms in 11 genes were 188 
added to the study (1, 2, 5, 10, 13, 20, 22, 23, 26, 28, 32, 34, 35), as detailed in the 189 
table below. 190 
 191 
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The rationale for SNPs selection 192 
Selection Procedure dbSNP rsID Gene (variant annotation) Chromosome Associated trait Base reference
Primary selection rs17602729 AMPD1 (nonsense) 1 Endurance traits (4, 15, 29) 
Primary selection rs8192678 PPARGC1A (missense) 4 Endurance traits (24) 
Primary selection rs2016520 PPARD (UTR 5) 6 Endurance traits (3) 
Primary selection rs8031031 GABPB1 (intron) 15 Endurance traits (6, 19) 
Primary selection rs7181866 GABPB1 (intron) 15 Endurance traits (9, 19, 25) 
Primary selection rs12594956 GABPB1 (intron) 15 Endurance traits (6, 7) 
Primary selection rs699 AGT (missense) 1 Power traits (17) 
Primary selection rs2070744 NOS3 (intron) 7 Power traits (16) 
Primary selection rs1805086 MSTN (missense) 2 Both traits (endurance and power) (11, 21, 33) 
Primary selection rs1815739 ACTN3 (nonsense) 11 Both traits (endurance and power) (36) 
Primary selection rs1799752 ACE (indel) 17 Both traits (endurance and power) (12, 14, 27) 
Secondary selection rs1870377 KDR (missense) 4 Endurance traits (1) 
Secondary selection rs35796750 COL6A1 (intron) 21 Endurance traits (28) 
Secondary selection rs1801282 PPARG (missense) 3 Power traits (2) 
Secondary selection rs1423560 FST (intron) 5 Power traits (22) 
Secondary selection rs1800169 CNTF (intron) 11 Power traits (34) 
Secondary selection rs10783486 ACVR1B (intron) 12 Power traits (35) 
Secondary selection rs2854464 ACVR1B (UTR 3) 12 Power traits (35) 
Secondary selection rs7136446 IGF1 (intron) 12 Power traits (20) 
Secondary selection rs1805065 SLC6A2 (missense) 16 Power traits (23) 
Secondary selection rs1049434 SLC16A1 (missense) 1 Both traits (endurance and power) (10, 32) 
Secondary selection rs11549465 HIF1A (missense) 14 Both traits (endurance and power) (5, 13) 
Secondary selection rs11091046 AGTR2 (UTR 3) X Both traits (endurance and power) (26) 
The primary selection was composed of polymorphisms used in the first studies that assessed the polygenic profile of endurance or power athletes(8, 30, 193 
31). The secondary selection was composed of polymorphisms identified after an electronic search of the scientific literature. 194 
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