doi:10.1152/japplphysiol.00310.2009 107:76-79, 2009. First published 28 May 2009;J Appl PhysiolChen Yamin, Michael Sagiv, Ehud Goldhammer and José OliveiraNir Eynon, Moran Sagiv, Yoav Meckel, José Alberto Duarte, Alberto Jorge Alves,endurance athletes' status

intron 3 A/G polymorphism is associated withNRF2

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NRF2 intron 3 A/G polymorphism is associated with endurance athletes’status

Nir Eynon,1,2 Moran Sagiv,1,2 Yoav Meckel,1 Jose Alberto Duarte,2 Alberto Jorge Alves,2 Chen Yamin,1,2

Michael Sagiv,1 Ehud Goldhammer,3 and Jose Oliveira2

1Genetics and Molecular Biology Laboratory, Life Sciences Division, The Zinman College of Physical Education and SportSciences at Wingate Institute, Netanya, Israel; 2Research Centre in Physical Activity, Health and Leisure, Faculty of Sport,University of Porto, Porto, Portugal; and 3Heart Institute, Bnai-Zion Haifa Medical Center, and Medical Faculty at theTechnion, Haifa, Israel

Submitted 22 March 2009; accepted in final form 21 May 2009

Eynon N, Sagiv M, Meckel Y, Duarte JA, Alves AJ, YaminC, Sagiv M, Goldhammer E, Oliveira J. NRF2 intron 3 A/Gpolymorphism is associated with endurance athletes’ status. J ApplPhysiol 107: 76–79, 2009. First published May 28, 2009;doi:10.1152/japplphysiol.00310.2009.—The aim of this study was todetermine the frequency distribution of nuclear respiratory factor 2(NRF2) intron 3 A/G polymorphism (rs7181866) among 155 Israeliathletes (endurance athletes and sprinters) and 240 healthy controls.Results showed that there was a significantly higher proportion of theAG genotype, rather than the AA genotype, in the group of enduranceathletes compared with the sprinters (P � 0.014) and controls (P �0.0008). However, the sprinters’ genotype and allele frequencies weresimilar to those of the control group (P � 0.62 for genotype distri-bution percentage). These results were even more pronounced when wecompared between the subgroups of 20 elite endurance athletes (thosewho had represented Israel in a world track-and-field championship or inthe Olympic Games) and 54 national-level endurance athletes. In thegroup of elite endurance athletes the G allele was more frequent than inthe national-level endurance athletes (P � 0.047). We conclude that 1) inIsraeli athletes the NRF2 AG genotype is more frequent in elite endur-ance athletes than in sprinters, and 2) within the endurance group theNRF2 AG genotype and the G allele are more frequent in elite athletes,suggesting a positive association between the AG genotype, and possiblythe G allele, and the likelihood of being an elite endurance athlete.

genetics; endurance athletes; sprinters

ENDURANCE EXERCISE induces an increase in several componentsof the mitochondrial respiratory chain and in enzymes involvedin fatty acid oxidation (19). This change appears to be medi-ated, at least partly, by increases in mitochondrial synthesis ofproteins (12) and results in high mitochondrial density and sizein skeletal muscles. However, despite considerable research,the mechanism by which endurance exercise stimulates mito-chondrial biogenesis is still poorly understood (2).

The nuclear respiratory factor 2 (NRF2) is a transcriptionfactor first discovered as the human homolog of the mouseGA-binding protein (GABP). A structure analysis of the NRF2subunits revealed a high degree of sequence identity with themouse GABP subunits (26, 27). It was suggested that theNRF2 together with nuclear respiratory factor 1 (NRF1) inducemitochondrial biogenesis (14, 23) and play an important role innucleo-mitochondrial interactions (13). NRF2 binding sites arefound in the promoter regions of several nuclear genes encod-

ing mitochondrial proteins, including cytochrome c, compo-nents of all five electron transport chain complexes, mitochon-drial import proteins, and heme biosynthesis proteins (10).Additionally, NRF2 regulates transcription factor A, a nuclear-encoded transcription factor essential for replication and tran-scription of mitochondrial DNA (9, 17).

The �1-subunit of the NRF2 gene (GABPB1) is located on15q21.2. A genomewide scan for maximal oxygen uptake(VO2max) suggested that this chromosome localization might beassociated with elevated VO2max in response to endurancetraining (3). In this sense, mild association was recently foundbetween oxygen uptake and A/G polymorphism in intron 3 ofthe �1-subunit of the NRF2 gene (11). In this polymorphismthe G allele was found to be associated with higher values ofoxygen uptake in response to endurance training. Interestingly,this association was significant only when it was consideredtogether with other polymorphisms in the NRF2 gene, usinghaplotype analysis (11). This is the only available informationregarding the plausible effect of polymorphisms in the NRF2gene on endurance training.

Due to the putative role of the NRF2 gene in the process ofmitochondrial transcription and regulation, and its potentialinfluence on endurance performance, the purpose of this studywas to analyze the frequency distribution of NRF2 intron 3A/G polymorphism (rs7181866) in athletic and nonathleticIsraeli populations and to compare the frequency distributionof the above polymorphism between athletes of sports withdifferent demands (endurance vs. sprinters) as well as betweencompetitive levels (elite level vs. national level).

MATERIALS AND METHODS

Subjects. One hundred and fifty-five athletes (119 men and 36women, age � 35.9 � 12.2 yr) volunteered to participate in the study.Athletes were included in the study sample only if they had partici-pated in national/international track-and-field championships. Ath-letes were divided into two groups: 1) an endurance-type group thatincluded 74 long distance runners whose main events were the10,000-m run and the marathon, and 2) a sprinttype group thatincluded 81 sprinters whose main event was the 100- or 200-m dash.According to their individual best performance, athletes within eachgroup were further divided into two subgroups: elite athletes (thosewho had represented Israel in a world track-and-field championship orin the Olympic Games) and national-level athletes. The control groupconsisted of 240 nonathletic healthy individuals (170 men and 70women, age � 26 � 3 yr) who were randomly selected from theIsraeli population. Controls were not engaged in physical activity ona regular basis. All subjects, athletes and nonathletes, were IsraeliCaucasians for �3 generations, with an equivalent ratio of Jews

Address for reprint requests and other correspondence: N. Eynon, Geneticsand Molecular Biology Laboratory, Life Sciences Division, The ZinmanCollege of Physical Education and Sport Sciences at the Wingate Institute,42902 Netanya, Israel (e-mail: eynon@wincol.ac.il).

J Appl Physiol 107: 76–79, 2009.First published May 28, 2009; doi:10.1152/japplphysiol.00310.2009.

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coming from Arab countries (non-Ashkenazi) and Jews coming fromEurope (Ashkenazi) in each group (2:1 ratio, respectively). The studywas approved by the Helsinki Committee of the Hillel-Yaffe MedicalCenter, Hadera, Israel, according to the Declaration of Helsinki. Awritten informed consent was obtained from each participant. Thestudy conformed to the standards set by the latest revision of theDeclaration of Helsinki.

Genotyping. Genomic DNA was extracted from peripheral EDTAtreated anticoagulated blood using a standard protocol. Genotyping ofthe NRF2 A/G polymorphism was performed using polymerase chainreaction (PCR) according to the method described by He et al. (11).Briefly, a 483-bp fragment of NRF2 was amplified by PCR usingNRF2 primers, forward (F) 5�-AGTTTAGTGTCTCCCAGTGT-3�and reverse (R) 5�-CTTAGTTTTCTTGTATCCGT-3�. PCR was per-formed by denaturation at 94°C for 5 min, 35 cycles of denaturationat 94°C for 1 min, annealing at 50°C for 1 min, extension at 72°C for1 min, and a final extension step of 10 min at 72°C. The amplifiedfragment subsequently underwent digestion by Rsa1 (New EnglandBiolabs, Beverly, MA) in a condition recommended by the supplier.The digested products were then electrophoresed in a 2.5% agarosegel. This method yields 284-bp and 199-bp fragments in the presenceof the A allele, and 483-bp in the presence of the G allele. ThePPARGC1A Gly482Ser polymorphism was amplified using PCRprimers F 5�-TAAAGATGTCTCCTCTGATT-3� and R 5�-GGAGA-CACATTGAACAATGAATAGGATTG-3�. PCR was performed bydenaturation at 95°C for 8 min, 40 cycles of denaturation at 94°C for45 s, annealing at 50°C for 45 s, extension at 72°C for 2 min, and afinal extension step of 10 min at 72°C. The amplified fragmentsubsequently underwent digestion by HPAII (New England Biolabs).This method yields a 378-bp fragment in the presence of the Ser482allele, and 209 and 169 bp in the presence of the Gly482 allele. Toensure proper internal control, for each genotype analysis we usedpositive and negative controls from different DNA aliquots that werepreviously genotyped with the same method, according to recentrecommendations for replicating genotype-phenotype associationstudies (5). The restriction fragment length polymorphism (RFLP)results were scored by two experienced and independent investigatorswho were blind to the subject data.

Data analysis. The SPSS statistical package, version 15.0, wasused to perform all statistical evaluations (SPSS, Chicago, IL, USA).A �2-test was used to confirm that the observed genotype frequencieswere in Hardy-Weinberg equilibrium and to compare alleles andgenotype frequencies between athletes and controls as well as be-tween athletes from different sports and from different competitivelevels. If observed or expected values included a cell with a value �5, we used Fisher’s exact test to compare alleles and genotypefrequencies. We also used a �2-test to examine the interaction betweenthe NRF2 A/G and the PPARGC1 Gly/Ser genotypes in relation toendurance performance. A logistic regression analysis was set to calcu-late the odds ratio for the interaction of both polymorphisms in enduranceathletes and in controls. The level of significance was set at P � 0.05.

RESULTS

The complete data on allele and genotype frequencies areshown in Table 1. The genotype subtype did not differ by ageor sex, as can be seen in Fig. 1. Since the Israeli populationincludes Caucasians who are mixed non-Ashkenazi and Ash-kenazi, we confirmed that there was an equivalent ratio ofsubjects of non-Ashkenazi and Ashkenazi descent in eachgroup (2:1), and that there were no differences across NRF2genotype between non-Ashkenazi and Ashkenazi descendants(�2 � 0.07, df � 2, P � 0.9). NRF2 genotype distribution wasin agreement with the Hardy-Weinberg equilibrium within theendurance athletes (P � 0.09), the sprinters (P � 0.68), and thecontrol group (P � 0.68). The endurance athletes’ genotype

frequencies differed from those of the sprinters and the controlgroup. We observed a significantly higher proportion of theAG genotype in the group of endurance athletes compared withthe sprinters and controls (see Table 1). However, the sprinters’genotype and allele frequencies were similar to those of thecontrol group (�2 � 0.24, df � 1, P � 0.62 for genotypedistribution percentage and �2 � 0.24, df � 1, P � 0.63 forallele frequency). A comparison between the national-levelendurance athletes and the control group revealed that the AGgenotype is more frequent in the national-level group (�2 �0.42, df � 1, P � 0.04 for genotype distribution percentageand �2 � 0.43, df � 1, P � 0.043 for allele frequency). Acomparison between the elite-level and national-level endur-ance athletes (see Fig. 2) revealed that the AG genotype andthe G allele were more frequently found in the elite enduranceathletes. Furthermore, the NRF2 AG � PPARGC1A Gly allelewas found to be the “optimal genotype” for endurance athleteswhen we compared them with the other genotypes (see Fig. 3).

In the cohort of endurance athletes, the odds ratio of theoptimal genotype (PPARGC1A Gly/Gly�Gly/Ser � NRF2AG) being an elite athlete was 14.75 (95% confidence interval3.37–64.5), and the odds ratio of the optimal genotype being anational-level endurance athlete was 6.02 (95% confidenceinterval 1.56–23.2).

DISCUSSION

The novel feature in the present study was the investigationof the frequency distribution of NRF2 A/G genotypes in eliteendurance and sprint athletes of different competitive levels.Our main finding was the overrepresentation of the NRF2 AGgenotype among the endurance athletes, particularly in the elitesubgroup, suggesting that the NRF2 A/G polymorphism maybelong to a growing group of genes that affect elite enduranceperformance (4).

The present study suggests that a tradeoff between endur-ance and sprint performance traits is possible, since 12% of theendurance athletes harbored the AG genotype compared withonly 2% in the sprinters and 2% in the control group. More-over, a specific comparison between the subgroups of elite- andnational-level athletes revealed that the NRF2 AG genotypewas more frequent in the group of elite endurance athletes.This suggests an increase in the NRF2 AG genotype andpossibly in the NRF2 G allele when higher-performing endur-ance athletes are genotyped. Our data are supported by anotherstudy (11) that previously reported on association between the

Table 1. Genotype and allele frequencies of NRF2 A/Gpolymorphism in all groups

Group n

Genotype Allele Frequency

AA AG Allele A Allele G

Endurance 74 65 (88%)*† 9 (12%)*† 139 (94%)‡§ 9 (6%)‡§Sprinters 81 80 (98%) 1 (2%) 161 (99%) 1 (1%)Control 240 235 (98%) 5 (2%) 475 (99%) 5 (1%)

Values are absolute (relative frequencies in parentheses). *�2 � 6.05, df �1, P � 0.014 for genotype frequencies in endurance athletes vs. sprinters;†�2 � 11.23, df � 1, P � 0.0008 for genotype frequencies in enduranceathletes vs. controls; ‡�2 �5.75, df � 1, P � 0.016 for allele frequency inendurance athletes vs. sprinters; §�2 � 10.97, df � 1, P � 0.0009 for allelefrequency in endurance athletes vs. controls.

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G allele and increased values of oxygen uptake in response toendurance training.

The NRF2 protein has been shown to play a key role ininducing many antioxidative enzymes (such as heme oxygen-ase-1) and diverse defensive genes against oxidative stress (16,21). In addition, enhanced expression of NRF2 has been shownto decrease expression of proinflammatory mediators, such asCox-2, interleukin-1�, interleukin-6, and TNF-�, in a micemodel (15). Thus it can be presumed that a higher expressionof NRF2 is advantageous for reaching higher athletic perfor-mance, since the magnitude of oxidative stress and inflamma-tory response induced by acute exercise is a considerable strainto the recovery ability following endurance exercise (20, 22,24). Additionally, NRF-2 sites have also been observed ingenes encoding the ATP synthase �-subunit (25, 27), which isin accordance with the well-established and decisive role of themitochondrial respiratory chain in producing the energy re-quired to sustain prolonged exercise, delaying the onset ofmuscle fatigue (6, 7).

Although aerobic exercise has a profound effect on proteinmetabolism, much less is known about the effect of aerobicexercise on NRF2 protein and/or mRNA activity. Baar et al. (2)reported a remarkable increase in muscle NRF2 protein levelsthat were evident 12–18 h following an acute bout of swimming,suggesting a rapid activation of this protein in response to endur-ance exercise. The transcription coactivator peroxisome prolifera-

tor-activated receptor coactivator-1� (PPARGC1A), which wasassumed to mediate the beneficial effects of exercise, was reportedto induce a two- to threefold increase in the expression of NRF2gene in response to endurance exercise (1). It seems that thesefindings may be relevant to the mechanism by which enduranceexercise induces increases in mitochondria biogenesis, sincethis implies that the NRF2 AG genotype, rather than the AAgenotype, may induce a greater increase in NRF2 proteinand/or mRNA levels, and thus is likely to improve enduranceperformance.

Up to this point several allelic variants have been associatedwith elite endurance performance (4). Among them is thePPARGC1A Gly482Ser polymorphism, which was previouslyfound to be associated with elite endurance performance by ourgroup (8) and others (18). PPARGC1A modulates muscleoxidative capacity via the coactivation NRF2 and other mito-chondrial proteins (28), and hence the interpretation of positiveassociation can be either that the NRF2 A/G polymorphismitself is responsible, or that it interacts with the PPARGC1AGly482Ser polymorphism, which in fact is responsible forthe observed associations with the NRF2 genotype. Indeed,in the present study we demonstrated an interaction betweenthese polymorphisms, and suggested that the NRF2 AG ge-notype together with the PPARGC1A Gly/Gly�Gly/Ser geno-types might be the “optimal genotype” for endurance athletes.

Fig. 3. Genotype frequencies of the “optimal genotype” for endurance athleteswithin the endurance athletes, the sprinters, and the control group. �2 � 19.8,df � 2, P 0.000 for genotype frequencies in PPARGC1 Gly/Gly�Gly/Ser �NRF2 AG vs. other genotypes between endurance athletes, sprinters, andcontrols.

Fig. 1. The NRF2 A/G genotype and allele frequenciesstratified by sex. �2 � 0.07, df � 1, P � 0.79 forgenotype frequencies in male vs. female within theendurance athletes; �2 � 0.27, df � 1, P � 0.6 forgenotype frequencies in male vs. female within thesprinters; �2 � 0.002, df � 1, P � 0.96 for genotypefrequencies in male vs. female within the controlgroup.

Fig. 2. The NRF2 A/G genotype and allele frequencies in elite-level andnational-level endurance athletes. �2 � 4.23, df � 1, P � 0.04 for genotypefrequencies in elite-level vs. national level endurance athletes; �2 � 3.95, df �1, P � 0.047 for allele frequencies in elite-level vs. national level enduranceathletes.

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It is important to remember that our positive results regarding theassociation between the G allele and elite endurance athletesmight be due to a low frequency of the minor G allele and/orpopulation stratification. However, the fact that our experimentalgroups did not contain any GG homozygous is in accordance withthe study of He et al. (11) and data from the NCBI (http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs��7181866) regard-ing Chinese and Europeans, respectively.

In conclusion, our data suggest an association between theNRF2 AG genotype and the G allele and elite enduranceathletes and further support the concept that harboring theNRF2 AG genotype and the NRF2 G allele may confer anadvantage to elite endurance athletes. However, further inves-tigation, such as comprehensive sequencing of this region aswell as functional studies, is needed to clarify just how thispolymorphism contributes to the endurance phenotype.

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