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Peroxisome proliferator-activated receptor alpha (PPARα) is involved in lipid and carbohydrate metabolism. The aim of this study was to test for a possible association between the PPARA intron 1 A/C polymorphism (rs135539) and the attainment of elite athlete status. In total, 155 Israeli athletes (119 males, 36 females) and 240 healthy controls (170 males, 70 females) participated in the study. The group of athletes consisted of endurance athletes (n=74) and sprinters (n=81). Genotyping was performed using PCR-RFLP on DNA from leucocytes. Results showed that genotype distribution and allele frequencies were similar (P=0.65 for genotypes and P=0.48 for allele frequency) for the endurance athletes (allele frequency A/C 0.7/0.3), sprinters (allele frequency A/C 0.66/0.34), and controls (allele frequency A/C 0.71/0.29). Furthermore, no significant differences were observed between the sub-groups of elite endurance athletes (those who had represented Israel in world track-and-field championships or in...

Nuclear respiratory factor 2 (NRF2), a member of the Cap-N-Collar family of transcription factors, plays an important role in the mitochondrial biogenesis, and variants of NRF2 gene have been associated with endurance performance. The aims of the present study were 1) to compare NRF2 A/C (rs12594956) and NRF2 C/T (rs8031031) genotype and allele frequencies between athletes of sports with different demands (endurance vs. sprinters) as well as between competitive levels (elite level vs. national level) and 2) to analyze the interaction of these two polymorphisms and its influence on the level of endurance performance. One hundred and fifty-five track and field athletes (74 endurance athletes and 81 sprinters) and 240 nonathletic healthy individuals participated in this study. Endurance athletes presented a higher frequency of the AA (rs12594956) and CT (rs8031031) genotypes than sprinters and the control group, as well as higher A and T alleles, respectively. These differences did not appear between the sprinters and control subjects. The odds ratio for harboring the “optimal genotype” ( NRF2 AA+ NRF2 CT) was 4.53 (95% confidence interval 1.23–16.6) in the whole cohort of endurance athletes and 6.55 (95% confidence interval 1.12–38.25) in elite-level endurance athletes, compared with control subjects and both levels of sprinters. In conclusion, our data indicate that the NRF2 A/C and NRF2 C/T single nucleotide polymorphisms (SNPs) are associated, separately and in combination, with elite endurance athletes, which supports the notion that these specific gene variants might belong to a growing group of SNPs that are associated with endurance performance.

Gene variants, such as creatine kinase (CK) polymorphisms, have been suggested to explain the inter-individual blood CK response to eccentric exercise. However, since this association is still doubtful, the purpose of this study was to analyse the relationship between the magnitudes of the CK response to exercise with the occurrence of muscle CK-MM NcoI polymorphism in young healthy subjects. Blood CK activity was assessed in 70 subjects immediately before and 3, 24, 48, 72, 96, 120, 168 h after strenuous eccentric exercise. Based on the amount of CK release by each subject, the sample was distributed in quartiles and the genotype and allele frequency distribution was compared among quartiles. Despite the inter-individual variability of CK response observed between subjects, there were no differences in genotype and allele frequencies among quartiles. The results allowed us to conclude that CK response after exhaustive eccentric exercise is not associated with CK-MM Ncol polymorphism.

A functional C825T polymorphism in the human guanine nucleotide binding protein beta polypeptide 3 (GNB3) gene has been associated with enhanced G protein activation. Since reports regarding the interaction between physical activity and the GNB3 C825T polymorphism are limited and inconsistent, the aim of this study was to determine the frequency of C825T alleles among 155 elite Israeli athletes (endurance athletes and sprinters) and 234 healthy control subjects. Genotyping for GNB3 C825T was performed using polymerase chain reaction on DNA from leucocytes. Results showed that there was a significant difference in GNB3 C825T polymorphism genotype frequencies between endurance athletes and sprinters (P = 0.045) as well as between endurance athletes and control subjects (P = 0.046). We also observed a significantly higher proportion of the GNB3 TT genotype in the group of endurance athletes (19%) compared with the sprinters (5%, P = 0.014) and the control subjects (8.5%, P = 0.026). In the group of athletes, the odds ratio of GNB3 TT genotype being an endurance athlete was 4.49 (95% confidence interval 1.4-14.3) and of GNB3 CC genotype was 0.91 (95% confidence interval 0.47-1.77). These results were even more pronounced when we compared between the subgroups of 20 top-level endurance athletes and 24 top-level sprinters. We conclude that in Israeli athletes the GNB3 TT genotype is higher in elite endurance athletes than it is in sprinters, and within the endurance group it is higher in top-level athletes, suggesting a positive association between the TT genotype and the likelihood of being an elite endurance athlete.

Exertional rhabdomyolysis is a complex and poorly understood entity. The inflammatory system has an important role in muscle injury and repair. Serum creatine kinase (CK) is often used as systemic biomarker representing muscle damage. Considerable variation exists in CK response between different subjects. Genetic elements may act as predisposition factors for exertional rhabdomyolysis. Based on their biological activity, we hypothesized that in healthy subjects IL6 G-174C and TNFA G-308A promoter polymorphisms would be associated with CK response to exercise. We determined serum CK activity pre- and post-maximal eccentric contractions of the elbow flexor muscles. IL6 G-174C and TNFA G-308A genotypes were analyzed for possible relationship with changes in serum CK activity. IL6 G-174C genotype was associated with CK activity in a dose-dependent fashion. Subjects with one or more of the -174C allele had a greater increase and higher peak CK values than subjects homozygous for the G allele (mean +/- SE U/L: GG, 2,604 +/- 821; GC, 7,592 +/- 1,111; CC, 8,403 +/- 3,849, ANOVA P = 0.0003 for GG + GC genotypes versus CC genotype, P = 0.0005 for linear trend). IL6-174CC genotype was associated with a greater than threefold increased risk of massive CK response (adjusted odds ratio 3.29, 95% confidence interval 1.27-7.85, P = 0.009). A milder association (P = 0.06) was noted between TNFA G-308A genotype and CK activity. In conclusion, we found a strong association of the IL6 G-174C genotype with systemic CK response to strenuous exercise. Data suggest that homozygosity for the IL6-174C allele is a clinically important risk factor for exercise-induced muscle injury, further supporting the central role of cytokines in the reactive inflammatory process of muscle damage and repair.

Unaccustomed exercise may cause muscle breakdown with marked increase in serum creatine kinase (CK) activity. The skeletal muscle renin-angiotensin system (RAS) plays an important role in exercise metabolism and tissue injury. A functional insertion ( I)/deletion ( D) polymorphism in the angiotensin I-converting enzyme ( ACE) gene (rs4646994) has been associated with ACE activity. We hypothesized that ACE ID genotype may contribute to the wide variability in individuals' CK response to a given exercise. Young individuals performed maximal eccentric contractions of the elbow flexor muscles. Pre- and postexercise CK activity was determined. ACE genotype was significantly associated with postexercise CK increase and peak CK activity. Individuals harboring one or more of the I allele had a greater increase and higher peak CK values than individuals with the DD genotype. This response was dose-dependent (mean ± SE U/L: II, 8,882 ± 2,362; ID, 4,454 ± 1,105; DD, 2,937 ± 753, ANOVA, P = 0.02; P = 0.009 for linear trend). Multivariate stepwise regression analysis, which included age, sex, body mass index, and genotype subtypes, revealed that ACE genotype was the most powerful independent determinant of peak CK activity (adjusted odds ratio 1.3, 95% confidence interval 1.03–1.64, P = 0.02). In conclusion, we indicate a positive association of the ACE ID genotype with CK response to strenuous exercise. We suggest that the II genotype imposes increased risk for developing muscle damage, whereas the DD genotype may have protective effects. These findings support the role of local RAS in the regulation of exertional muscle injury.

An Alu insertion (I)/deletion (D) polymorphism in the angiotensin I converting enzyme (ACE) gene has been associated with ACE activity. Opposing effects on elite athletic performance have been proposed for the I and D alleles; while the D allele favours improved endurance ability, the I allele promotes more power-orientated events. We tested this hypothesis by determining the frequency of ACE ID alleles amongst 121 Israeli top-level athletes classified by their sporting discipline (marathon runners or sprinters). Genotyping for ACE ID was performed using polymerase chain reaction on DNA from leucocytes. The ACE genotype and allele frequencies were compared with those of 247 healthy individuals. Allele and genotype frequencies differed significantly between the groups. The frequency of the D allele was 0.77 in the marathon runners, 0.66 in the control subjects (P = 0.01) and 0.57 in the sprinters (P = 0.002). The ACE DD genotype was more prevalent among the endurance athletes (0.62) than among the control subjects (0.43, P = 0.004) and the power athletes (0.34, P = 0.004). In the group of elite athletes, the odds ratio of ACE DD genotype being an endurance athlete was 3.26 (95% confidence interval 1.49-7.11), and of ACE II genotype was 0.41 (95% confidence interval 0.14-1.19). We conclude that in Israeli elite marathon runners the frequency of the ACE D allele and ACE DD genotype seems to be higher than in sprinters, suggesting a positive association between the D allele and the likelihood of being an elite endurance athlete in some ethnic groups.

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates gene expression in response to hypoxia and has been associated with athletic performance. The aims of this study were (1) to determine the frequency distribution of HIF1A Pro582Ser (rs11549465) polymorphism among 155 Israeli athletes (sprinters and endurance athletes) and 240 healthy controls and (2) to analyze the influence of the interaction between HIF1A Pro582Ser and ACTN3 R577X (rs1815739) genotypes on sprint performance. There were no differences across the HIF1A genotype and allele frequencies among endurance athletes, sprinters, and controls. Similarly, no differences were found between the subgroups of top-level and national-level endurance athletes, or between top-level and national-level sprinters. Conversely, interaction effects were found between HIF1A Pro582Ser and ACTN3 R577X polymorphisms and sprinters. The proportion of HIF1A Pro/Pro + ACTN3 R/R genotypes was significantly higher in sprinters than in endurance athletes and healthy controls (P = .002). In addition, the odds ratio for HIF1A Pro/Pro + ACTN3 R/R genotype carriers being a sprinter was 2.25 (95% confidence interval, 1.24-4.1); and that for HIF1A Pro/Pro + ACTN3 R/R genotype carriers being an endurance athlete was 0.5 (95% confidence interval, 0.2-1.24). We conclude that HIF1A Pro582Ser polymorphism by itself is not critical in determining sprint performance. However, sprinter performance is determined by the interaction between the wild-type HIF1A Pro/Pro genotype and ACTN3 RR genotype.

Functional Gly482Ser (rs8192678) and T294C (rs2016520) polymorphisms in the peroxisome proliferator-activated receptor gamma coactivator-1 (PPARGC1A) and peroxisome proliferator-activated receptor delta (PPARD) genes, respectively, have been associated with mRNA and/or protein activity. The aim of this study was to determine their frequency distribution among 155 Israeli athletes (endurance athletes and sprinters) and 240 healthy control subjects. There were no differences between the endurance athletes, the sprinters and the control group across the PPARD T294C genotypes (P = 0.62). Similarly, no statistical differences were found between the subgroups of elite-level endurance athletes (those who had represented Israel in a world track and field championship or in the Olympic Games) and national-level endurance athletes (P = 0.3), or between elite-level and national-level sprinters (P = 0.9). However, a combined influence of these two polymorphisms on endurance performance was found. The PPARD CC + PPARGC1A Gly/Gly genotypes were more frequently found in the elite endurance athletes than in national-level endurance athletes (P0.000). In the cohort of endurance athletes, the odds ratio of the 'optimal genotype' for endurance athletes (PPARD CC + PPARGC1A Gly/Gly + PPARGC1A Gly/Ser) being an elite-level athlete was 8.32 (95% confidence interval 2.2-31.4). In conclusion, the present study suggests that PPARD T294C is not associated with endurance performance. However, a higher frequency of the PPARGC1A Gly/Gly + PPARD CC genotype is associated with elite-level endurance athletes.

The aim of this study was to determine the frequency distribution of nuclear respiratory factor 2 ( NRF2) intron 3 A/G polymorphism (rs7181866) among 155 Israeli athletes (endurance athletes and sprinters) and 240 healthy controls. Results showed that there was a significantly higher proportion of the AG genotype, rather than the AA genotype, in the group of endurance athletes compared with the sprinters ( P = 0.014) and controls ( P = 0.0008). However, the sprinters’ genotype and allele frequencies were similar to those of the control group ( P = 0.62 for genotype distribution percentage). These results were even more pronounced when we compared between the subgroups of 20 elite endurance athletes (those who had represented Israel in a world track-and-field championship or in the Olympic Games) and 54 national-level endurance athletes. In the group of elite endurance athletes the G allele was more frequent than in the national-level endurance athletes ( P = 0.047). We conclude that 1) in Israeli athletes the NRF2 AG genotype is more frequent in elite endurance athletes than in sprinters, and 2) within the endurance group the NRF2 AG genotype and the G allele are more frequent in elite athletes, suggesting a positive association between the AG genotype, and possibly the G allele, and the likelihood of being an elite endurance athlete.

A functional C825T polymorphism in the human guanine nucleotide binding protein beta polypeptide 3 (GNB3) gene has been associated with enhanced G protein activation. Since reports regarding the interaction between physical activity and the GNB3 C825T polymorphism are limited and inconsistent, the aim of this study was to determine the frequency of C825T alleles among 155 elite Israeli athletes (endurance athletes and sprinters) and 234 healthy control subjects. Genotyping for GNB3 C825T was performed using polymerase chain reaction on DNA from leucocytes. Results showed that there was a significant difference in GNB3 C825T polymorphism genotype frequencies between endurance athletes and sprinters (P = 0.045) as well as between endurance athletes and control subjects (P = 0.046). We also observed a significantly higher proportion of the GNB3 TT genotype in the group of endurance athletes (19%) compared with the sprinters (5%, P = 0.014) and the control subjects (8.5%, P = 0.026). In the group of athletes, the odds ratio of GNB3 TT genotype being an endurance athlete was 4.49 (95% confidence interval 1.4-14.3) and of GNB3 CC genotype was 0.91 (95% confidence interval 0.47-1.77). These results were even more pronounced when we compared between the subgroups of 20 top-level endurance athletes and 24 top-level sprinters. We conclude that in Israeli athletes the GNB3 TT genotype is higher in elite endurance athletes than it is in sprinters, and within the endurance group it is higher in top-level athletes, suggesting a positive association between the TT genotype and the likelihood of being an elite endurance athlete.

An Alu insertion (I)/deletion (D) polymorphism in the angiotensin I converting enzyme (ACE) gene has been associated with ACE activity. Opposing effects on elite athletic performance have been proposed for the I and D alleles; while the D allele favours improved endurance ability, the I allele promotes more power-orientated events. We tested this hypothesis by determining the frequency of ACE ID alleles amongst 121 Israeli top-level athletes classified by their sporting discipline (marathon runners or sprinters). Genotyping for ACE ID was performed using polymerase chain reaction on DNA from leucocytes. The ACE genotype and allele frequencies were compared with those of 247 healthy individuals. Allele and genotype frequencies differed significantly between the groups. The frequency of the D allele was 0.77 in the marathon runners, 0.66 in the control subjects (P = 0.01) and 0.57 in the sprinters (P = 0.002). The ACE DD genotype was more prevalent among the endurance athletes (0.62) than among the control subjects (0.43, P = 0.004) and the power athletes (0.34, P = 0.004). In the group of elite athletes, the odds ratio of ACE DD genotype being an endurance athlete was 3.26 (95% confidence interval 1.49-7.11), and of ACE II genotype was 0.41 (95% confidence interval 0.14-1.19). We conclude that in Israeli elite marathon runners the frequency of the ACE D allele and ACE DD genotype seems to be higher than in sprinters, suggesting a positive association between the D allele and the likelihood of being an elite endurance athlete in some ethnic groups.