Medicine & Science in Sports & Exercise:
The Human Gene Map for Performance and Health-Related Fitness Phenotypes: The 2006-2007 Update
BRAY, MOLLY S.1; HAGBERG, JAMES M.2; PÉRUSSE, LOUIS3; RANKINEN, TUOMO4; ROTH, STEPHEN M.2; WOLFARTH, BERND5; BOUCHARD, CLAUDE4
1USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX; 2Department of Kinesiology, School of Public Health, University of Maryland, College Park, MD; 3Division of Kinesiology, Department of Preventive Medicine, Laval University, Ste-Foy, Québec, CANADA; 4Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA; and 5Preventive and Rehabilitative Sports Medicine, Technical University Munich, Munich, GERMANY
Address for correspondence: Claude Bouchard, Ph.D., Human Genomics Laboratory, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808-4124; E-mail: email@example.com.
Submitted for publication April 2008.
Accepted for publication June 2008.
ABSTRACT: This update of the human gene map for physical performance and health-related fitness phenotypes covers the research advances reported in 2006 and 2007. The genes and markers with evidence of association or linkage with a performance or a fitness phenotype in sedentary or active people, in responses to acute exercise, or for training-induced adaptations are positioned on the map of all autosomes and sex chromosomes. Negative studies are reviewed, but a gene or a locus must be supported by at least one positive study before being inserted on the map. A brief discussion on the nature of the evidence and on what to look for in assessing human genetic studies of relevance to fitness and performance is offered in the introduction, followed by a review of all studies published in 2006 and 2007. The findings from these new studies are added to the appropriate tables that are designed to serve as the cumulative summary of all publications with positive genetic associations available to date for a given phenotype and study design. The fitness and performance map now includes 214 autosomal gene entries and quantitative trait loci plus seven others on the X chromosome. Moreover, there are 18 mitochondrial genes that have been shown to influence fitness and performance phenotypes. Thus, the map is growing in complexity. Although the map is exhaustive for currently published accounts of genes and exercise associations and linkages, there are undoubtedly many more gene-exercise interaction effects that have not even been considered thus far. Finally, it should be appreciated that most studies reported to date are based on small sample sizes and cannot therefore provide definitive evidence that DNA sequence variants in a given gene are reliably associated with human variation in fitness and performance traits.
In this seventh installment of the human gene map for performance and health-related fitness phenotypes published in this journal, we cover the peer-reviewed literature published by the end of December 2007. The focus of the review is on the new material published in 2006 and 2007. The search for relevant publications is primarily based on the journals available in MEDLINE, the National Library of Medicine's publication database covering the fields of life sciences, biomedicine, and health using a combination of key words (e.g., exercise, physical activity [PA], performance, training, genetics, genotype, polymorphism, mutation, linkage). Electronic prepublications, that is, articles that are made available on the Web site of a journal before being published in print are not included in the current review if there were not available in print by the end of December 2007. The literature search is limited to articles published in English, French, German, and Finnish.
The goal of the human gene map for fitness and performance is to review all genetic loci and markers shown to be related to physical performance or health-related fitness phenotypes in at least one study. Negative studies are briefly reviewed for a balanced presentation of the evidence. However, the nonsignificant results are not incorporated in the summary tables. Although this review focuses on the advances reported in 2006 and 2007, the summary tables are meant to represent a full compendium of all positive findings reported to date for a given fitness or performance phenotype and a particular study design.
The physical performance phenotypes for which genetic data are available include cardiorespiratory endurance, elite endurance athlete status, muscle strength, other muscle performance traits, and exercise intolerance of variable degrees. Consistent with the previous reviews, the phenotypes of health-related fitness are grouped under the following categories: hemodynamic traits including exercise heart rate (HR), blood pressure (BP), and heart morphology; anthropometry and body composition; insulin and glucose metabolism; and blood lipid, lipoprotein, and hemostatic factors. Here, we are not concerned about the effects of specific genes on these phenotypes unless the focus is on exercise, exercise training, athletes or active people compared with controls or inactive individuals, or exercise intolerance. For instance, genetic studies that have focused on body mass index (BMI), adiposity, fat-free mass, adipose tissue distribution, or various abdominal fat phenotypes are not considered unless there was an exercise-related issue addressed in the articles.
The studies incorporated in the review are fully referenced so that the interested reader can access the original articles. Of interest to some could be the early observations made on athletes, particularly Olympic athletes. The results of these early case-control studies typically based on common red blood cell antigens or enzymes were essentially negative and are not reviewed in this edition of the map. The interested reader can consult the first installment of the gene map for a complete summary of these early reports (235).
The 2007 synthesis of the human performance and health-related fitness gene map for the autosomes and the sex chromosomes is summarized in Figure 1. The 2007 update includes 239 gene entries and quantitative trait loci (QTL), 52 more than the 2005 depiction of the map. We have also depicted in Figure 2 the mitochondrial genes that have been shown to be associated with fitness and performance phenotypes. Table 1 provides a list of all genes or loci, cytogenic locations, and conventional symbols used in this review. The terminology and the symbols used are as defined in the legend to Table 1.
In 2007, an expert panel from the National Cancer Institute and the National Human Genome Research Institute of the US National Institutes of Health published a comprehensive set of recommendations on factors to consider in evaluating genotype-phenotype association reports in assessing the soundness of an initial association report and in establishing the conditions for valid replication studies (36). The report contains a wealth of information on what constitutes high-quality association studies with complex human traits. Some of the topics raised are of particular importance to those interested in evaluating the quality of the information available on specific genes and fitness and performance phenotypes. These topics have to do with sample size, quality of the phenotype measurement, quality of the exercise or activity exposure, study design, adjustment for multiple testing, population stratification, publication biases, genotyping errors, and replication studies.
Most studies reviewed in this inventory were underpowered to establish a definitive genotype-phenotype relationship. Because the effect size of a given gene on fitness or performance-related traits is generally small, the sample size necessary to achieve a significant risk ratio with a credible, very small P value is quite high, well above 1000 and preferably above 10,000 cases with as many controls. The optimal sample size will vary depending on whether the phenotype is precisely and reliably measured; the less error variance, the lower the sample size. The same is true for the "exposure to exercise" variable. If the study deals with the response to exercise and the subjects are exercise trained in a well-controlled and fully monitored laboratory environment, the sample size required to have sufficient power will be lower than in a situation where subjects are asked to exercise on their own at home during their leisure time. Even when a study generates a very small P value for the risk ratio associated with a genotype at a given gene, the results should be interpreted with caution until replication studies confirm the initial finding.
In assessing the quality of the studies reviewed in this inventory, the reader should also consider whether the threshold P value reported was adjusted for multiple testing, population stratification, or some other uncontrolled factor, including nonrandom genotyping errors, which could have created a spurious association. It is important to verify if the design of the study and the analytical approaches were appropriate and sufficiently described to allow replication in another laboratory. It is also useful to recognize that there is a very strong tendency to publish studies with positive results despite all their weaknesses. Indeed, in the end, very few negative studies reach publication. This strong bias precludes the use of published reports on a given gene-phenotype association to produce a meaningful meta-analysis with the hope that the latter will compensate somehow for the chronic lack of statistical power in the individual studies.
It remains our collective goal to make this publication a useful resource for those who teach undergraduate and graduate students about the role of inheritance on fitness and performance traits and the impact of genetic variation on health and prevention of diseases. It is our hope that these updates of the fitness and performance gene map will increase the interest and motivation of exercise scientists and physicians for genetic studies. It is also our hope that this compendium will motivate scientists from other fields to evaluate the contribution of exercise or leisure-time PA in their genetic studies.
A total of 10 articles from case-control studies were published in the 2006-2007 period (Table 2). The functional bradykinin beta 2 receptor (BDKRB2) −9/+9 polymorphism, which consists of the presence/absence of a 9-base pair (bp) repeat sequence in exon 1, was investigated in ironman triathlon athletes and healthy controls (267). The fast finishers of the triathlon showed a higher number of −9/−9 genotypes compared with the controls. The nitric oxide synthase 3 (NOS3) G894T genotypes were also investigated for association in this athlete group, and a significant linear trend of increasing frequency of the G/G genotypes among tertiles of the triathlon finishers from fastest to slowest was observed. The same linear trend was observed for the combined +9/+9 and GG multivariate genotype groups. In addition, the combination of −9/−9 genotypes and G-allele carriers of the NOS3 polymorphism was significantly higher in the fast triathletes (267).
Two case-control studies found significant results for the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism. Hruskovicova et al. (110) reported significantly different genotype and allele distributions between elite marathon runners and in-line marathoners compared with a group of sedentary controls. In Israeli endurance athletes, a higher number of D-allele carriers and D/D genotypes was seen comparing those athletes to healthy individuals (P = 0.01), with an even higher level of significance for the comparison with sprint athletes (P = 0.002) (5). Significantly different genotype frequencies (P < 0.0001) were reported for the intron 7 G/C genetic variant in the peroxisome proliferator-activated receptor alpha (PPARA) gene between endurance- and power-oriented athletes and nonathlete controls. In addition, the authors reported an association between the intron 7 G/C genotypes and the muscle fiber type distribution, with G/G homozygotes having a significantly higher percentage of slow-twitch fibers (P = 0.003) (3). Wolfarth et al. (344) compared elite endurance athletes with sedentary controls for the Arg16Gly polymorphism in the beta 2 adrenergic receptor (ADRB2) gene. An excess of Gly-allele carriers was seen in the sedentary controls indicating a negative association of this allele with respect to the performance status.
Three different case-control cohorts were investigated with respect to the actinin alpha 3 (ACTN3) gene R577X polymorphism. None of the articles reported different allele or genotype distributions comparing professional cyclists, ironman triathletes, and a mixed group of different Italian athletes with healthy controls (163,209,266). The distribution of the ACE I/D polymorphism was investigated in Korean male elite athletes, but no difference in genotype or allele distribution was found between this group and unrelated nonathletes (200). Finally, in a South African cohort of ironman triathlon athletes, there was no difference for the growth hormone 1 (GH1) 1663 T > A polymorphism genotype frequencies for 155 control subjects in comparison to the 169 fastest finishers of the triathlon event (331).
Cross-sectional association studies
V˙O2max and vascular endothelial growth factor A (VEGFA) haplotype data were analyzed by Prior et al. (223) in 148 white and black subjects (Table 3). Besides an association of these haplotypes with V˙O2max before and after training, they were able to show an impact of the gene polymorphisms on VEGFA gene expression in human myoblasts. In a large cohort of CAD patients, the associations of two beta 1 adrenergic receptor (ADRB1) gene polymorphisms, Ser49Gly and Gly389Arg, were tested before and after 3 months of exercise training. They found an association between the Ser49Gly polymorphism and the haplotypes of the Ser49Gly and the Gly389Arg polymorphisms with aerobic power but not with the response to physical training (51). In premenopausal sedentary women, different measures of body composition and performance were obtained and analyzed for association with variation in the insulin-like growth factor 1 (IGF1) gene. Results showed that carriers of a 189-bp allele of a CT repeat (IGF1189) perform better in activities requiring exercise economy and endurance performance (157). Dekany et al. (53) investigated 74 subjects analyzing exercise efficiency associated with the ACE I/D polymorphism. They described the ACE I-allele as a genetic marker for higher endurance efficiency in acute physical activities. Tanabe et al. (295) examined the ACE I/D genotype for association with clinical characteristics and survival. D-allele carriers also had a significantly lower 6-min walk test distance compared with homozygotes for the I-allele (330 ± 102 vs 381 ± 85 m; P < 0.046). This association remained when only the medically treated patients were examined, with D carriers having a mean distance of 337 ± 92 m compared with 418 ± 62 m for the I/I homozygotes (P < 0.05) (295).
Polymorphisms in several xenobiotic metabolizing enzyme genes, glutathione S transferase pi (GSTP1), microsomal epoxide hydrolase (EPHX1), transforming growth factor beta 1 (TGFB1), serpin peptidase inhibitor E2 (SERPINE2), and surfactant, pulmonary-associated protein B (SFTPB), were examined for association to exercise capacity phenotypes in patients with emphysema enrolled in the National Emphysema Treatment Trial. Maximal exercise capacity was determined for all subjects via the use of cycle ergometry. Single nucleotide polymorphisms (SNP) in EPHX1 (rs1877724 and rs1051740) were associated with maximum work and low exercise capacity (P = 0.0002-0.03), whereas polymorphisms in LTBP4 (rs2303729, rs1131620, rs1051303, and rs2077407) were associated with maximum work (P = 0.0001-0.03), low exercise capacity (P = 0.0001-0.02), and 6-min walking test distance (P = 0.04-0.05). A short tandem repeat marker in the SFTPB gene (D2S388) was associated with low exercise capacity (P = 0.05) and 6-min walking test distance (P = 0.005) in these patients (106).
In addition, four articles with pure cross-sectional approaches showed no significant associations of endurance phenotypes and different polymorphisms in ADRB2 (285), NOS3 (96), ACE (45), and solute carrier family 6 (neurotransmitter transporter, serotonin) member 4 (SLC6A4) (265) genes.
Association studies with training response phenotypes
In the HERITAGE Family Study, a peroxisome proliferator-activated receptor delta (PPARD) polymorphism was associated with physical performance. In black subjects, the exon 4 + 15 C/C (rs2016520) homozygotes showed a smaller training-induced increase in maximal oxygen consumption compared with the C/T and the T/T genotypes. Similarly, in black subjects, a lower training response in maximal power output was observed in the exon 4 + 15 C/C homozygotes compared with carriers of the T-allele. In white subjects, a similar trend was observed (99). In a lifestyle intervention study of diet and PA, the rs2267668 SNP in the PPARD and the Gly482Ser polymorphism in the peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PPARGC1A) gene showed associations with the changes in anaerobic threshold (289). The authors reported lower anaerobic threshold response in carriers of the G-allele of SNP rs2267668 compared with the A/A genotype. Less increase in anaerobic threshold was also observed in carriers of the Ser482-encoding allele compared with the Gly/Gly genotype (P < 0.004). In addition, the authors reported evidence for additive effects of the PPARD and the PPARGC1A SNP on the effectiveness of aerobic exercise training to increase anaerobic threshold (289). In an 18-wk training study with 102 recruits from China, two polymorphisms in the hemoglobin beta (HBB) gene were associated with the training response of running economy (103). In the same cohort, associations between V˙O2max values and beta 2 subunit of GA binding protein transcription factor (GABPB2) genotype were observed for the rs12594956, rs8031031, and rs7181866 loci. Individuals carrying the ATG haplotype of all three loci had 57.5% greater exercise training-related improvement in running economy (measured as V˙O2 during submaximal exercise) than noncarriers (102).
Three ACE articles showed associations in the context of training response. Seventeen Korean women participated in a 12-wk endurance training program. The ACE T3892C polymorphism was significantly associated with the response in V˙O2max after the endurance training. Angiotensinogen (AGT) and angiotensin II receptor type 1 (AGTR1) and type 2 (AGTR2) polymorphisms showed no association with the training effects (16). A study with 933 CAD patients from the CAREGENE cohort showed an independent association of the ACE I/D polymorphism with the aerobic power response to physical training in favor of the I/I genotype (52). A Turkish cohort of 55 nonathlete females trained three times per week for 6 wk. The major measurements were 30-min running performance and other submaximal measures. The authors report an association of the ACE I/I genotype with better improvements in medium duration aerobic endurance performance, whereas ACE D/D genotype was more advantageous for shorter duration and higher intensity activities (32). In an investigation of the muscle creatine kinase (CKM) NcoI polymorphism after an 18-wk 5000-m running program, Zhou et al. (356) reported a significant increase in running economy and adaptation to training for the A/G genotype compared with the A/A and G/G genotypes.
Polymorphisms of the mitochondrial transcription factor A were investigated before and after an 18-wk controlled endurance training program in Chinese nonathletes. They found no association and concluded that these polymorphisms do not predict endurance capacity or its trainability in Chinese male (101). Two more studies investigated endurance phenotypes before and after training targeting polymorphisms in the muscarinic 2 cholinergic receptor (CHRM2) gene and a promoter polymorphism in the apolipoprotein A1 (APOA1) gene. Both studies found no associations with V˙O2max at baseline or after the training intervention (100,259).
No new linkage studies on performance-related phenotypes were published in 2006-2007 (Table 4).
Muscle Strength Phenotypes
In 2006-2007, three studies reported case-control associations for athletes specializing in strength-related or anaerobic performance activities. All such studies are shown in Table 5, although some crossover exists with Table 2 for those studies that also include endurance athletes.
Ahmetov et al. (3) investigated the intron 7 G/C polymorphism in the peroxisome proliferator-activated receptor alpha (PPARA) gene in 786 Russian male and female athletes and 1242 controls. The genotype frequencies did not differ between athletes and controls when sport stratification was ignored; however, when sport stratification was considered, a higher C-allele frequency was observed in anaerobic power athletes compared with controls (P < 0.001) as well as a lower C-allele frequency in aerobic athletes (P = 0.029). This finding was observed in both men and women. Analysis of muscle fiber type in a subset of 40 control men revealed significantly lower type I fiber proportions in the C/C genotype carriers (P < 0.001).
Yang et al. (351) studied the ACTN3 gene locus and its nonsense R577X polymorphism in African athletes and examined X-allele frequencies in relation to African controls. The authors did not observe any significant genotype frequency differences between Nigerian sprinters and controls, although the very low X-allele frequency in this population prevented complete analysis. Nonetheless, the authors were able to conclude that the low X-allele frequency in the population in general points to at most a limited role for this polymorphism in African athletes.
An examination of the ACE I/D polymorphism in Korean athletes and controls did not yield significant results, although the 139 male athletes had heterogeneous sport backgrounds, which limited analysis against the 163 controls (200).
The studies reporting candidate gene associations with muscle strength or anaerobic performance phenotypes are summarized in Table 6. In 2006-2007, 16 studies reported positive genetic associations with muscle strength-related phenotypes, although several studies reported mixed findings for specific genes or polymorphisms within gene regions.
The ACTN3 gene and its nonsense R577X polymorphism has generated considerable attention in the past few years and was the focus of three association studies in this area in 2006-2007. Moran et al. (184) examined 40-m sprint performance in 992 Greek adolescents genotyped for the ACTN3 R/X polymorphism. Male, but not female, carriers of the X/X genotype exhibited slower sprint times compared with R/R carriers (P = 0.003), as shown in Figure 3. Delmonico et al. (56) examined knee extensor concentric peak power before and after a 10-wk unilateral knee extensor strength training intervention in 157 older men and women. In women, X/X carriers exhibited greater baseline relative peak power (at 70% of one repetition maximum [1RM]) than both R/X and R/R genotypes (both P < 0.01) but a lower change in relative peak power in response to the training compared with the R/R group (P = 0.02). In men, no genotype differences were observed at baseline, but the change in absolute peak power in response to training tended to be higher in R/R compared with X/X genotypes (P = 0.07). Vincent et al. (322) studied the ACTN3 R577X polymorphism in relation to isometric and isokinetic knee extensor strength in 90 young men and observed lower concentric peak torque at 300°·s−1 in X/X compared with R/R homozygotes (P = 0.04). In a subset of these subjects, the authors also reported a lower proportion of type IIx muscle fibers in X/X vs R/R homozygotes (P < 0.05).
Three studies examined the ACE I/D genotype in relation to a variety of strength-related measures. Moran et al. (182) examined handgrip strength and vertical jump in 1027 Greek teenagers and identified significantly higher handgrip strength and vertical jump scores (both P < 0.001) in females carrying the I/I genotype. No significant associations were observed in the males for either performance measure. The authors performed haplotype analysis of the ACE gene region using three polymorphisms and determined that the I/D polymorphism explained the bulk of the explained genetic variance. Pescatello et al. (216) studied the ACE I/D genotype in relation to elbow flexor strength before and after unilateral upper arm strength training in 631 young men and women. They reported no association with muscle strength at baseline in either arm but reported greater improvements in isometric strength (MVC) in the trained arm after training in carriers of the I-allele (P < 0.01). Consistently, MVC increased in the untrained arm after training only in I-allele carriers (P < 0.01), with no change in D/D genotype carriers. In a biomechanical analysis, Wagner et al. (328) examined leg press strength variables and used discriminant analysis to determine the association of the ACE I/D genotype with muscle performance in 62 young men and women. The researchers showed that no single muscle phenotype was consistently associated with ACE I/D genotype, but that combinations of traits including contraction velocity, isometric force, and optimum contraction velocity could discriminate the three genotype groups with substantial accuracy in both men (P = 0.02) and women (P = 0.03). In these analyses, the I/I genotype carriers exhibited lower maximum and optimum contraction velocity compared with the I/D and the D/D genotype groups.
The vitamin D receptor (VDR) locus was the focus of two studies. Windelinckx et al. (342) examined the BsmI, TaqI, and FokI VDR polymorphisms in 493 middle-aged and older men and women for association with various muscle strength measures. FokI was analyzed independently, whereas BsmI and TaqI were combined in a haplotype analysis. In women, the FokI polymorphism was associated with quadriceps isometric (P < 0.05) and concentric (P = 0.06) strength, with higher levels in f/f homozygotes compared with F-allele carriers. In men, the BsmI/TaqI haplotype was associated with quadriceps isometric strength (P < 0.05), with Bt/Bt homozygotes exhibiting greater strength than bT haplotype carriers. Wang et al. (334) examined the ApaI, BsmI, and TaqI VDR polymorphisms in 109 young Chinese women in relation to knee and elbow torque measures. At the ApaI locus, A/A women exhibited lower elbow flexor concentric peak torque compared with a/a carriers (P < 0.04) as well as lower knee extensor eccentric peak torque compared with both A/a and a/a carriers (P < 0.01). For the BsmI locus, the b/b carriers demonstrated lower knee flexor concentric peak torque (180°·s−1) than the B-allele carriers (P = 0.03). No associations were observed for the TaqI locus.
Ciliary neurotrophic factor (CNTF)-related genes were the focus of two reports in 2006-2007. Arking et al. (13) examined eight polymorphisms surrounding the CNTF locus, including the rare rs1800169 nonsense polymorphism (A/G; A = null allele), in 363 older Caucasian women. Haplotype analysis revealed a significant association with handgrip strength, which was completely explained by the rs1800169 A-allele, such that individuals homozygous for the null A-allele (n = 16) exhibited lower handgrip strength compared with A/G and G/G genotypes (P < 0.006). De Mars et al. (49) examined multiple polymorphisms at both the CNTF and the CNTF receptor (CNTFR) loci in a study of 493 middle-aged and older men and women with measures of knee flexor and extensor strength. T-allele carriers of the C-1703T CNTFR polymorphism exhibited higher strength levels for multiple measures compared with CC homozygotes (all P < 0.05), including all knee flexor torque values. In middle-aged women, A-allele carriers at the T1069A CNTFR locus exhibited lower concentric knee flexor peak torque at multiple speeds and isometric torque at 120° compared with T/T homozygotes (all P < 0.05). The CNTF null allele was not associated with any strength measures nor were any CNTF × CNTFR interactions observed.
The study of De Mars et al. (49) is one of several that examined groups of genes within a physiological pathway in relation to strength phenotypes. For example, Walsh et al. (332) examined the genetic association of haplotype structure in the myostatin receptor, activin-type II receptor B (ACVR2B), and follistatin (a myostatin inhibitor) loci with muscle strength and mass phenotypes in 593 men and women across the adult age span. In women but not men, ACVR2B haplotype was significantly associated with knee extensor concentric peak torque (P = 0.04). Although follistatin haplotype was associated with leg fat-free mass in men, no associations were observed with muscle strength. Hand et al. (95) examined promoter region polymorphisms in insulin-like growth factor (IGF) pathway genes in relation to the response of muscle strength and volume to strength training in 128 older men and women. The genes under study included insulin-like growth factor 1 (IGF1), calcineurin (PPP3R1), and insulin-like growth factor binding protein 3 (IGFBP3). The IGF1 gene promoter CA repeat polymorphism was associated with the one-repetition maximum (1RM) response to strength training (P < 0.01), and a possible interaction with the PPP3R1 I/D polymorphism was noted (P = 0.07). The −202 A/C polymorphism in IGFBP3 was not associated with any phenotype. Hopkinson et al. (107) examined the bradykinin type 2 receptor (BDKRB2) gene as well as the ACE I/D polymorphism in relation to quadriceps strength in 110 chronic obstructive pulmonary disease (COPD) patients. A 9-bp insertion/deletion polymorphism (−9/+9) in the BDKRB2 gene was associated with quadriceps isometric strength (MVC), with lower values for +9/+9 homozygotes compared with −9-allele carriers (P = 0.02), although the association appeared to be driven by higher fat-free mass in +9/+9 homozygotes (P = 0.04). As these authors also showed previously (108), the ACE D-allele was associated with greater quadriceps MVC compared with II homozygotes in the present study, but no BDKRB2 × ACE interaction was observed, indicating independent influences of these two genes on muscle strength phenotypes.
Pistilli et al. (221) examined six polymorphisms in the resistin gene in relation to muscle and bone phenotypes in 482 young white men and women who performed upper-arm strength training. With regard to strength phenotypes, the 398 C/T polymorphism was significantly associated with training-induced change in 1RM (T/T > C/T and C/C; P < 0.05) and MVC (C/C > C/T; P = 0.04) in women. In men, the −420 C/G polymorphism was associated with the training-induced change in 1RM (P = 0.03) and MVC (P = 0.03), with C/C homozygotes having greater responses compared with G/G carriers; the 540 G/A polymorphism was also associated with the training-induced change in 1RM strength (P < 0.05), with G/G carriers greater than A/A carriers. Fischer et al. (69) examined the adenosine monophosphate deaminase 1 (AMPD1) gene, in which multiple rare polymorphisms result in AMP deaminase deficiency in approximately 2% of Caucasians. Anaerobic performance was measured during a 30-s Wingate cycle test in 139 men and women, 12 of whom were AMP deaminase deficient. Deficient subjects exhibited a more rapid decline in power output (P < 0.001) and a lower mean power (P = 0.004) compared with other genotypes. Finally, Devaney et al. (59) studied the association of several polymorphisms in the insulin-like growth factor 2 (IGF2) gene in relation to exertional muscle damage of the elbow flexors in 151 young men and women. After a damaging eccentric contraction protocol, loss of isometric strength in response to the damaging exercise protocol was significantly different among genotype groups for multiple polymorphisms in the IGF2 gene region (P < 0.05).
No new linkage studies were published in 2006-2007 (Table 4).
HEALTH-RELATED FITNESS PHENOTYPES
During 2006 and 2007, 17 studies were published that assessed the impact of genetic variants on hemodynamic responses to acute exercise (Table 7). Snyder et al. (285) studied the cardiovascular (CV) hemodynamics of 64 young Caucasian men at rest and during a continuous exercise protocol consisting of 9 min at 40% and another 9 min at 75% of their peak cycle ergometer work rate. They fairly consistently found that Arg16/Arg16 genotype individuals at the Arg16Gly ADRB2 locus had lower plasma norepinephrine levels and lower cardiac output (Q˙), stroke volume (SV), and mean arterial pressure at both work rates compared with Gly16/Gly16 genotype individuals.
Nieminen et al. assessed the effect of several genes on heart rate (HR) and blood pressure (BP) responses to exercise in 890 middle- to older-age men and women in the Finnish CV Study (199). Their Gly389 homozygotes at the ADRB1 gene locus had higher maximal exercise systolic BP (P = 0.04) and a greater change in systolic BP from rest to maximal exercise (P = 0.03) than heterozygotes and Arg homozygotes at this locus. Furthermore, in women, Gly389 homozygotes had lower maximal exercise HR than the two other genotype groups (P = 0.04). They also found that Arg homozygotes at this locus were less likely to have ventricular extrasystoles during exercise (odds ratio [OR] = 0.68, P = 0.009) than Gly-allele carriers at this locus. They also reported a tendency for the ADRB1 Ser49Gly polymorphism to affect exercise HR (P = 0.06). The T393C polymorphism at the GNAS1 gene locus significantly affected the HR response during exercise and recovery (P = 0.04).
Kim et al. (136) studied 269 Japanese hypertensives and found that a hypertensive response to maximal exercise (systolic BP >210 mm Hg in men and >190 mm Hg in women) was significantly more frequent in G/G homozygotes at the NOS3 Glu298Asp locus (P = 0.016). In fact, this difference in exercise-induced hypertension was primarily accounted for by genotype-dependent response differences in women (P < 0.001), whereas there was not a significant association in the men. Also, in the G/G homozygote women, the increase in systolic BP from rest to maximal exercise was significantly greater than that in women who were T-allele carriers at this locus (49 ± 23 vs 34 ± 13 mm Hg; P < 0.001).
The effect of the alpha adducin 1 (ADD1) Gly460Trp polymorphism on ambulatory BP after 30 min of exercise at both 40% and 60% V˙O2max in 48 overweight, hypertensive Caucasian men was studied by Pescatello et al. (215). They found that heterozygotes at this locus elicited greater reductions in 9-h ambulatory systolic BP after 40% V˙O2max exercise than Gly homozygotes (−7.8 ± 2.3 vs −0.6 ± 1.3 mm Hg; P < 0.05). They reported no significant effects of this variant on ambulatory diastolic BP after exercise at either intensity or on ambulatory systolic BP changes after the higher intensity exercise. In addition, they found that plasma renin levels increased significantly more after the 60% V˙O2max exercise (7.3 ± 1.3 vs 2.7 ± 2.2 μU·mL−1; P < 0.05) but not after the 40% V˙O2max exercise (3.1 ± 0.8 vs 2.0 ± 1.4 μU·mL−1; P > 0.05) in Gly homozygotes compared with heterozygotes at this locus.
Pescatello et al. (217) investigated the effects of several renin-angiotensin system polymorphic variants and their interaction with dietary calcium intake on ambulatory BP after 30 min of cycle ergometer exercise at 40% and 60% V˙O2max in 50 men with high normal BP or stage 1 hypertension. During the intake of a low-calcium diet, systolic BP reductions after 40% V˙O2max (3.5 vs 9.8 mm Hg; P < 0.05) and 60% V˙O2max exercise (5.7 vs 2.6 mm Hg; P < 0.05) differed between the ACE I-allele carriers and D homozygotes, respectively. Diastolic BP did not differ between ACE genotype groups after either exercise intensity under these conditions. Also during the low-calcium diet, the systolic BP reductions after 60% V˙O2max exercise differed between AGTR1 A homozygotes and C-allele carriers (7.5 vs 2.1 mm Hg; P < 0.05), whereas no such differences were evident for systolic BP after 40% V˙O2max exercise or for diastolic BP after either exercise intensity. During high dietary calcium intake, ACE I/D genotype again significantly affected systolic BP (P < 0.05) and tended to affect the diastolic BP response (P = 0.065) after the 60% V˙O2max exercise, but no such differences were evident after the 40% V˙O2max exercise. During high-calcium dietary intake, systolic BP reductions after 60% V˙O2max exercise tended to differ between AGTR1 A homozygotes and C-allele carriers (6.9 vs 1.2 mm Hg, respectively; P = 0.086) with no such differences being evident for diastolic BP after this exercise intensity or either systolic or diastolic BP after the lower intensity exercise.
Blanchard et al. (20) studied the effects of several genetic variants within the renin-angiotensin-aldosterone system on ambulatory BP after 30 min of cycle ergometer exercise at 40% and 60% V˙O2max in 47 men with pre- to stage 1 hypertension. In men, homozygosity for the ACE D-allele systolic BP after the 40% V˙O2max exercise was significantly lower compared with men carrying at least one ACE I-allele (128 ± 2 vs 132 ± 3 mm Hg; P = 0.047). They found no effect of ACE genotype on systolic BP after the 60% V˙O2max exercise or on diastolic BP after either intensity of exercise. The AGTR1 A/C and aldosterone synthase (CYP11B2) intron 2 W/C variants did not independently influence systolic or diastolic BP responses after 40% or 60% V˙O2max exercise. Individuals carrying variant alleles at all three of these loci had significantly lower systolic (128 ± 3 vs 133 ± 3 mm Hg; P = 0.03) and diastolic BP (79 ± 2 vs 83 ± 2 mm Hg; P = 0.00) after 40% V˙O2max exercise. The number of variant alleles carried by participants did not significantly affect either systolic or diastolic BP after the 60% V˙O2max exercise.
In a unique study, Scharin Tang et al. (270) investigated the impact of the ADRB1 Ser49Gly variant in the transplanted heart in 20 heart transplant patients on HR responses during a cycle ergometer test. They found a tendency for individuals with a Gly homozygote transplanted heart to have greater HR responses to maximal cycle ergometer exercise than individuals with transplanted hearts carrying at least one Ser allele at this locus (64 ± 13 vs 47 ± 16 beats·min−1; P = 0.056).
Leineweber et al. (152) studied the effect of the ADRB1 Arg389Gly gene variant on the hemodynamic responses of 16 Caucasian men to supine cycle ergometer exercise while also undergoing atropine blockade. They found that HR, left ventricular (LV) contractility, plasma renin activity, and systolic and diastolic BP responses to the exercise were the same between genotype groups, whereas at the two highest work rates, plasma norepinephrine responses were significantly greater in Gly compared with Arg homozygotes at this locus (473 ± 154 vs 215 ± 166 pg·mL−1; P = 0.013).
Ueno et al. (314) studied the impact of the ADRA2B 12Glu9 variant on cardiac autonomic responses to sustained handgrip exercise in 78 normotensive obese women. They found that Glu12 homozygotes and heterozygotes increased mean BP and HR with handgrip exercise (both P < 0.05), whereas the Glu9 homozygotes did not increase either mean BP or HR with handgrip exercise. The same trends were evident with normalized low-frequency components assessed by R-R interval power spectral analysis increasing during exercise in Glu12 carrier groups but not Glu9 homozygotes. In fact, during the handgrip exercise, Glu12 carriers had higher normalized low-frequency component levels on power spectral analysis than Glu9 homozygotes. On the other hand, normalized high-frequency components decreased with exercise in Glu12 homozygotes but not the other two genotype groups (314).
Hand et al. (96) assessed the effects of two NOS3 genotypes on submaximal and maximal exercise hemodynamic responses in 62 Caucasian postmenopausal women of differing PA levels. NOS3 T-786C genotype did not significantly influence BP, HR, cardiac output (Q˙), stroke volume (SV), arterial-venous oxygen difference (a-vO2diff), or total peripheral resistance (TPR) during submaximal or maximal exercise when averaged across all habitual PA levels. However, NOS3 G894T genotype significantly or tended to affect submaximal exercise diastolic BP (P = 0.06), HR (P = 0.007), and SV (P = 0.03) and maximal exercise HR (P = 0.04) and SV (P = 0.08) when averaged across all PA groups. Systolic BP, Q˙, a-vO2diff, and TPR during submaximal exercise and systolic and diastolic BP, Q˙, a-vO2diff, and TPR during maximal exercise were not significantly associated with NOS3 G894T genotype when averaged across all habitual PA groups.
Arena et al. (12) studied HR responses after supine leg ergometer exercise in 40 patients with hereditary hemochromatosis who were homozygous for a C282Y hemochromatosis (HFE) gene mutation compared with 21 age- and gender-matched healthy controls. The patients were found to have a significantly smaller reduction in HR 1 min after the exercise test compared with the healthy control subjects (29 ± 9 vs 35 ± 9 beats·min−1; P < 0.01). No other differences were noted between the groups for peak exercise HR, systolic BP, or double product.
Perhonen et al. (214) in Finland studied the responses of seven symptomatic potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) G589D missense mutation carriers, which cause the familial long QT syndrome LQT1 subtype, to a maximal cycle ergometer exercise test. They found that the patients had a lower maximal HR than healthy controls (160 ± 3 vs 180 ± 2 beats·min−1; P < 0.05). However, the patients had similar resting HR, left ventricular (LV) mass, and resting LV ejection fraction as the healthy controls.
Ashley et al. (14) assessed the effect of the ACE I/D polymorphism on the degree to which 85 highly trained athletes (23 women, 62 men) reduced their LV function after a 300-mile race requiring many modes of exercise; the range of times required to complete the event was 84-110 h. Interestingly, these authors did not find an excess of ACE I-alleles in this highly trained endurance athlete population. However, individuals homozygous for the ACE I-allele experienced a significantly greater decline in LV ejection fraction after the event compared with D-allele homozygotes (approximately −14% vs −6%; P = 0.017); heterozygotes had responses intermediate between the two homozygote groups. ACE genotype did not have a significant effect on diastolic function changes after the event. ACE genotype differentially affected the changes in autonomic function after the event as measured by BP spectral analyses with a significant decline in the high-frequency domain in D/D genotype individuals (P < 0.01). There tended to be an increase in the low-frequency domain in BP spectral analysis in D/D individuals (P = 0.06), whereas I/I and I/D genotype individuals showed no change in this domain.
Hautala et al. (100) studied the effects of six SNP within the CHRM2 locus on HR recovery after a maximal exercise test in 80 Finnish men and women. SNP in CHRM2 were not associated with maximal HR but did influence HR recovery after exercise. Individuals homozygous for the T-allele at the rs324640 locus exhibited significantly greater HR recovery 1 min after maximal exercise (−40 ± 11 beats·min−1; P = 0.008) than heterozygotes (−33 ± 7 beats·min−1) or homozygotes for the C-allele at this locus (−33 ± 10 beats·min−1). In addition, A-allele carriers at the rs8191992 locus showed significantly less HR recovery after exercise than T homozygotes at this locus (P = 0.025). Similar trends were seen for systolic BP, but the differences were not significant. Haplotypes constructed based on the rs8191992 and the rs324640 SNP showed generally stronger statistical trends for these same hemodynamic phenotypes.
Zateyshchikov et al. (353) studied the effects of common variants in the CYP2D6 and ADRB1 genes on exercise responses in 81 essential hypertensive patients undergoing treatment with betaxalol. They found that the Pro34Ser genotype affected some hemodynamic responses to maximal exercise with heterozygotes having greater reductions in maximal exercise HR (−30 ± 3 vs −24 ± 3 beats·min−1; P = 0.043) and maximal exercise diastolic BP (−13 ± 1 vs −9 ± 2 mm Hg; P = 0.022) with betaxalol treatment than Ser homozygotes. However, they did not find any significant effects of Ser49Gly and Arg389Gly ADRB1 genotypes on hemodynamic responses to maximal exercise in these individuals before or after betaxalol treatment.
In addition to performing genome-wide linkage scans (see Linkage studies section), Ingelsson et al. (115) also assessed genotype associations for 235 SNP in 14 putative CV genes relative to exercise treadmill test responses in 2982 participants in the Framingham Offspring Study. They found the following nominal associations: ADRA1A (rs489223) and exercise systolic BP (P = 0.004); AGT (rs2493136; P = 0.003), ADRA1D (rs835873; P = 0.008), and exercise diastolic BP; ACE (rs4305; P = 0.01), ADRA1A (rs544215; P = 0.005), ADRA1D (rs3787441; P = 0.007), and exercise HR; ADRA1A (rs483392; P = 0.005), ADRA1A (rs7820633; P = 0.005), and recovery systolic BP; ADRA1A (G2286a1) and recovery diastolic BP (P = 0.009); and ADRA1B (rs11953285) and recovery HR (P = 0.01). However, none of these associations remained significant after accounting for multiple testing.
Vasan et al. (320) performed a genome-wide association study for hemodynamic responses to acute treadmill exercise using 70,987 SNP in 1238 related middle- to older-age men and women in the original Framingham Study and the Framingham Offspring Study. In these analyses, the five strongest associations based on general estimating equations (additive genetic models) were rs6847149 (P = 2.74 × 10−6), rs2819770 (P = 3.53 × 10−6), and rs2056387 (P = 5.17 × 10−6) for stage 2 exercise HR; rs746463 (P = 4.88 × 10−6) for 3-min recovery systolic BP; and rs2553268 (P = 6.32 × 10−6) for stage 2 exercise systolic BP. The five strongest associations using family-based association tests were rs1958055 for stage 2 exercise HR (P = 8.55 × 10−6); rs7828552 (P = 9.34 × 10−6) and rs2016718 (P = 2.20 × 10−7) for recovery systolic BP; and rs1029947 (P = 9.20 × 10−7) and rs1029946 (P = 3.89 × 10−6) for recovery HR. However, none of these associations reached statistical significance after accounting for multiple testing.
During 2006 and 2007, three published studies assessed the interactive effect of genetic variants and PA levels on hemodynamic phenotypes (Table 7). Rankinen et al. (231) in the HYPGENE Study compared EDN1 genotype and haplotype frequencies between hypertensive cases (n = 607) and matched controls (n = 586). They found that two SNP (rs2070699 and Lys198Asn) significantly interacted with CV fitness to affect the risk of hypertension with the genotype-dependent relationship for both SNP being evident in the low-fit but not the high-fit individuals. Analyses of haplotypes constructed from these two SNP substantiated the significant effect of these SNP interacting with CV fitness on hypertension risk.
Grove et al. (85) assessed the impact of GNB3 C825T genotype interacting with habitual PA levels on a person's risk of developing hypertension in 14,716 blacks and whites in the Atherosclerosis Risk in Communities Study. They found a significant (P = 0.02) multiplicative interaction between GNB3 genotype, PA levels, and obesity on risk of hypertension in blacks. After accounting for race, obese 825T homozygotes with low levels of habitual PA had almost a threefold greater risk of being hypertensive (OR = 2.71, P = 0.018) than 825C homozygotes who were nonobese and physically active.
Hand et al. (96) assessed the effects of two NOS3 genotypes on submaximal and maximal exercise hemodynamic responses in 62 Caucasian postmenopausal women of differing PA levels. In this study, NOS3 G894T and T-786C genotypes did not interact significantly with habitual PA levels to influence BP, HR, Q˙, SV, a-vO2diff, or TPR during submaximal or maximal exercise in these women.
During 2006 and 2007, 10 published studies assessed the effect of genetic variants on hemodynamic responses to exercise training (Table 8). Rankinen et al. (231) in the HERITAGE Cohort assessed the effect of EDN1 genotypes and haplotypes on exercise training-induced changes in hemodynamic phenotypes to determine whether they supported their cross-sectional findings reported above in the HYPGENE Cohort. They found that in whites in the HERITAGE Cohort, two EDN1 SNP (Lys198Asn and rs4714383) were significantly associated with the training-induced responses of systolic BP and pulse pressure at a 50-W work rate. They also found that haplotypes across these two loci accounted for 2.6% and 3.5% of the interindividual variance in the training-induced responses of systolic BP and pulse pressure at a 50-W work rate, respectively, whereas the contribution of the individual SNP ranged from 0.8% to 1.7%.
Flavell et al. (70) studied the response of MRI-determined LV mass and BP to 10 wk of military training in young male army recruits. They sought to determine the effect of the lipoprotein lipase (LPL) S447X variant on these responses, and they found that X447 carriers showed a smaller increase in LV mass (2 ± 2% vs 6 ± 1%; P = 0.03) but a greater decrease in systolic BP (−6 ± 2 vs 2 ± 1 mm Hg; P = 0.015) in response to the training than men not carrying an X447 allele.
Jones et al. (119) assessed the impact of two common gene variants in the renin-angiotensin system on the changes in 24-h ambulatory BP and sodium (Na+) excretion with seven to eight consecutive days of exercise training in 31 hypertensive African Americans. Their ACE I/I genotype individuals increased 24-h Na+ excretion after the 7-8 d of exercise (114 ± 22 to 169 ± 39 mEq·d−1; P = 0.04), whereas no such increases were evident in the I/D or the D/D genotype individuals. ACE genotype did not significantly affect 24-h ambulatory BP, and the AGT M235T variant did not affect either 24-h ambulatory BP or Na+ excretion.
The impact of the fatty acid binding protein 2 (FABP2) Ala54Thr gene variant on BP changes after 3 months of a ifestyle intervention that included hypocaloric diet and exercise was studied in 69 obese men and women by de Luis et al. (46). They reported that individuals carrying at least one Thr allele at this locus decreased their systolic BP significantly with the lifestyle intervention (129 ± 12 to 122 ± 13 mm Hg; P < 0.05), whereas Ala homozygotes did not reduce their systolic BP. The FABP2 Ala54Thr variant did not affect diastolic BP responses to the lifestyle intervention.
He et al. (103) assessed the impact of 18 wk of endurance exercise training in 102 Chinese Han men on several performance-related variables which included exercise HR responses. They found that men homozygous for either the G- or C-allele at the intron 2 16G/C variant at the HBB locus decreased their HR during treadmill running at 12 km·h−1 more than men heterozygous at this locus (−5 ± 3 and −4 ± 4 vs −2 ± 6 beats·min−1; P < 0.05).
Cam et al. (32) studied the effects of 6 wk of endurance exercise training on performance measures and resting HR in 55 Caucasian nonelite Turkish women athletes. They reported that the ACE I/D polymorphism had no effect on the changes in resting HR elicited with training in these women.
Park et al. (210) studied the impact of the nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1) −94 I/D polymorphism relative to changes in endothelial function in humans with endurance exercise training. They found that with 6 months of endurance exercise training in 36 pre- and stage 1 hypertensive men and women, there was a tendency for greater improvements in reactive hyperemic forearm blood flow in NFKB1 I/I and I/D genotype individuals compared with D/D homozygotes at this locus (39 ± 43%, 6 ± 9%, and −13 ± 17% change in 3-min reactive hyperemic blood flow after training). They also found that the I/I genotype was significantly more frequent (31%, P = 0.047) and that the D/D genotype was significantly less frequent (4%, P = 0.006) among individuals who responded to exercise training with an improvement in reactive hyperemic blood flow response.
Perhonen et al. (214) in Finland studied the responses of seven symptomatic KCNQ1 G589D missense mutation carriers, which cause the familial long QT syndrome LQT1 subtype, to a maximal cycle ergometer exercise test before and after 3 months of endurance exercise training. With training, LV mass increased by 8-9% in both the patients and the healthy controls. In the patients, exercise training shortened resting QTc by 10 ± 1% (P < 0.05), whereas no changes in QTc occurred in the healthy controls. QT interval dispersion at rest after training decreased by 25 ± 9% in the patients (P < 0.05), whereas again no such decreases were evident in the healthy controls. The QTc at 5 min of recovery after the exercise test after training was reduced in the patients by 6 ± 2% (P < 0.05) with no such changes evident in the healthy control subjects.
As described above in the Acute exercise section, Hautala et al. (100) studied the effects of six SNP within the CHRM2 locus on HR recovery after a maximal exercise test in 80 Finnish men. However, in these same individuals, they also studied the impact of a 2-wk endurance exercise training program on numerous hemodynamic phenotypes. After training, HR recovery 1 min after maximal exercise was strongly associated with genotype at the rs324640 locus (P = 0.001), and the change in HR recovery with exercise training was significantly associated with genotype at this locus (−3 ± 7, 2 ± 7, and 2 ± 8 beats·min−1, for the C/C, C/T, and T/T genotypes, respectively; P = 0.038). Genotype at the rs8191992 locus also was significantly associated with HR recovery after training (P = 0.005). They also studied the effects of these variants on overnight HR variability assessed by power spectral analyses in these subjects and found that rs8191992 A/A homozygotes had a significantly higher low- to high-frequency domain ratio than other genotype groups at this locus both before (P = 0.036) and after training (P = 0.046).
During 2006 and 2007, two studies was published that assessed linkage and CV hemodynamic phenotype changes with exercise training (Table 9). An et al. (6) performed a genome-wide linkage scan using 654 markers to identify QTL for the response of resting HR to exercise training in the HERITAGE Cohort. In whites, they found multipoint linkages (P < 0.01, logarithm of odds [LOD] >1.18) for the change in resting HR with exercise training at the 1q42.2 and the 21q22.3 chromosomal loci. In blacks, linkage was detected at the 3p14.1, 3p14.2, 3p21.2, 20p11.23, and 21q21.1 chromosomal loci.
Ingelsson et al. (115) performed genome-wide scans for exercise treadmill test responses in 2982 participants in the Framingham Offspring Study. For systolic BP during submaximal exercise, they reported an LOD = 2.02 for chromosomal location 1q32.1, LOD = 1.57 for 5q13.2, and LOD = 1.61 for 10q23.3. Chromosomal location 19q13.1 was the only locus linked with diastolic BP during submaximal exercise (LOD = 1.63). Five loci were linked with HR during submaximal exercise: 1p32.1-31.1 (LOD = 1.91), 5q14.3 (LOD = 2.09), 7p15.1-14.3 (LOD = 1.73), 7q21.1 (LOD = 1.67), and 14q24.1 (LOD = 1.91). Chromosomes 1q43-44 (LOD = 2.59) and 2p12 (LOD = 1.68) showed linkage with systolic BP during recovery. Similarly, two loci were linked to diastolic BP during recovery (4p15.3, LOD = 2.37; and 4q28.2, LOD = 1.93) and another two were linked to HR during recovery (5q35.3, LOD = 1.60; and 21q21.1, LOD = 1.66).
Spielmann et al. (287) assessed the linkage of submaximal exercise HR to chromosomal loci at baseline and after 20 wk of exercise in the black and the white participants in the HERITAGE Family Study. They found that, in whites, there was linkage evidence for HR at a 50-W work rate at baseline at 18q21.33 (LOD = 2.64, P = 0.0002), at 2q33.3 (LOD = 2.13, P = 0.0009) for the training-induced changes in HR at 50 W, and at 18q21.1 (LOD = 2.10, P = 0.0009) for the training-induced change in HR at 60% V˙O2max. Five markers in the chromosomal region of 10q24-q25.3 showed evidence of linkage in blacks with HR responses to exercise (Table 9). Because two putative candidate genes (ADRB1 and ADRA2A) lie within this chromosomal region, the investigators performed association studies with 6 ADRA2A and 10 ADRB1 SNP and found that in their black subjects, the Arg389Gly ADRB1 SNP was significantly associated with baseline HR at 50 W in black siblings (P = 0.02) and in the whole cohort (P = 0.04).
Anthropometry and Body Composition Phenotypes
In the past 2 yr, seven studies tested the association between candidate genes and BMI, body composition, or bone mineral density (BMD) taking into account the interaction with physical activity (PA; Table 10). A study in 1068 men from the Gothenburg Osteoporosis and Obesity Determinants study revealed that a functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene, resulting in a lowered enzyme activity, modulated the association between PA and BMD assessed by dual-energy x-ray absorptiometry (158). A significant interaction (P < 0.0001) was found for whole-body mineral density, and stratified analyses revealed significant differences in BMD between high (≥4 h·wk−1) and low (< 4 h·wk−1) PA groups in subjects carrying the low-activity variant (Val159Met and Met158Met subjects) compared with subjects homozygous for the high-activity allele (Val158Val subjects), suggesting that the beneficial impact of PA on BMD is greater in the former than in the latter. In a sample of 1797 unrelated subjects (868 men and 929 women) from the Framingham Offspring cohort, Kiel et al. (134) tested the hypothesis that polymorphisms in the low-density lipoprotein receptor-related protein (LRP5) gene could modulate the relationship between PA and BMD. Significant evidence of interaction between SNP in exon 10 (rs2306862; P = 0.02) and exon 18 (rs3736228; P = 0.05) and PA on BMD of the spine was observed in men. Another study undertaken in 190 postmenopausal women revealed evidence of interaction between a polymorphism in a transcription factor Cdx-2 binding site in the promoter of the VDR gene and a PA on the femoral neck and Ward's triangle BMD (81).
In a large sample of 10,988 whites and 3728 blacks, Grove et al. (85) tested the interaction between the GNB3 825 C > T polymorphism and the PA level in relation to obesity. No significant evidence of interaction was found in whites, but a significant (P < 0.001) interaction was observed in blacks; the T-allele being associated with an increased risk of obesity in subjects with low PA level and a decreased risk in subjects with high PA level (85). In a study conducted in 899 women and 902 men aged between 30 and 75 yr, the PPARGC1A Gly482Ser polymorphism was found to be associated with an increased risk of obesity but only in physically inactive (< 2 h·wk−1) males aged ≥50 yr (248). However, the interaction between the polymorphism and the PA level was not statistically significant, and this result is this considered as a negative finding and, consequently, is not reported in Table 10. In other studies involving the PPARG Pro12Ala (195) polymorphism and polymorphisms in the PPARGC1A gene (194), no evidence of gene-PA interaction could be found for obesity-related phenotypes.
Response to exercise
We found seven studies that tested association with candidate genes and adiposity phenotypes in response to exercise and five reported positive findings (Table 10). In the first study, the effects of several SNP in the resistin (RETN) gene were tested for association with changes in upper arm subcutaneous fat and cortical bone volumes measured by magnetic resonance imaging before and after 12 wk of a resistance training program of the nondominant arm in 120 men and 203 women (221). No evidence of association was found with changes in subcutaneous fat, but two RETN SNP were associated with changes in the cortical bone volume in women (398 C > T and 980 C > G) and in men (980 C > G). In the second study, 84 Korean women with abdominal obesity were tested before and after 12 wk of aerobic (walking) exercise, and changes in body fat were found to be associated with a polymorphism (K121Q) in the gene ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) encoding the plasma cell membrane glycoprotein PC-1 (211). Women homozygotes for the K-allele exhibited greater reductions in body weight (P = 0.002) and BMI (P = 0.03) compared with women carrying the Q-allele.
The third study tested the association of body weight changes during ironman triathlons with polymorphisms in the ACE, BDKRB2, NOS3, and solute carrier family 6 (neurotransmitter transporter, and serotonin) member 4 (SLC6A4) genes in 428 triathletes (265). Two functional polymorphisms in the BDKRB2 and the SLC6A4 genes were found to be associated with larger weight losses in the triathletes. The fourth study investigated the association between the PPARA L162V polymorphism and the upper arm subcutaneous fat in response to resistance training in 610 young men and women (315). Increases in the fat volume of the untrained arm were observed in male (n = 146) carriers of the V-allele after exercise training compared with a decrease in subjects with the LL genotype. According to the authors, this finding is a consequence of the 78% increase in triglycerides found in the V-allele carriers compared with the homozygous genotype (315). In the fifth study, CT-assessed changes in intermuscular fat in response to 10 wk of single-leg strength training were examined in relation to polymorphisms in the ADRB2 and the ADRA2B genes in 98 men and women (352). Decreases in intermuscular fat were found to be significantly different between carriers and noncarriers of the ADRA2B Glu(9) polymorphism.
Two other studies provided negative findings. In one of these, the influence of the ADRB3 Trp64Arg polymorphism on weight loss after a 3-month lifestyle modification program was investigated in 65 obese patients (47). The program consisted of a hypocaloric diet combined with three sessions (60 min each) of aerobic exercise per week. Significant reductions of body weight, BMI, fat mass, and waist circumference were observed in both carriers and noncarriers of the Arg64 allele. Although the authors reported that carriers of the Arg64 allele had a different response than noncarriers, no evidence could be found in the data presented that the response was statistically different between the two genotype groups, as only differences between pre- and postvalues within each genotype group were reported (47). For that reason, and despite the claim of the authors, the results of this study are considered as negative. In another study using the same cohort and lifestyle modification program, de Luis et al. (48) investigated the influence of the LEPR Lys656Asn polymorphism on weight loss and leptin changes. As in the previous study, they reported a different response between body weight, BMI, and leptin levels between Lys656Lys subjects and carriers of the Asn allele, but no formal tests of the differences between the two genotype groups were reported.
No new linkage studies on anthropometry and body composition-related phenotypes were published in 2006-2007 (Table 11).
Insulin and Glucose Metabolism Phenotypes
In a study undertaken in 566 subjects, a significant interaction (P = 0.02) between PA and PPARG Pro12Ala polymorphism on the risk of T2DM was reported in subjects from families with T2DM (196). The authors found that the Pro12 allele was associated with an increased risk of T2DM (OR = 2.37), but only in subjects with low PA (Table 12).
Response to exercise
Using data from 481 participants of the Finnish Diabetes Prevention Study followed-up for an average of 4.1 yr, Laaksonen et al. (143) found an interaction (P = 0.03) between the ADRA2B 12Glu9 polymorphism, which consists of a deletion of 9 bp encoding three glutamic acid residues, and the changes in PA on the risk of developing T2DM. Increased PA was associated with a reduced risk of T2DM but only in subjects with the Glu12/12 (RR = 0.12) and Glu12/9 (RR = 0.30) genotypes. In another study based on data from the same cohort (135), the association of polymorphisms in the solute carrier family 2 (facilitated glucose transporter), member 2 (SLC2A2), ATP-binding cassette, subfamily C (CFTR/MRP), member 8 (ABCC8), and potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) genes with the conversion from impaired glucose tolerance (IGT) to T2DM according to changes in PA level was studied in 479 subjects. Three polymorphisms in the SLC2A2 gene as well as one polymorphism in the ABCC8 gene provided significant evidence of interaction with changes in moderate-to-vigorous PA (≥3.5 METs) in predicting the conversion from IGT to T2DM. In all cases, increased moderate-to-vigorous PA, independent of the changes in diet and body weight, was associated with a reduced risk of T2DM, but only in carriers of the common homozygous genotypes (135). The impact of lifestyle modification (dietary counseling and endurance exercise for 9 months) on changes in insulin sensitivity measured in 139 subjects was tested for association with polymorphisms in the PPARD (three SNP) and PPARGC1A (one SNP) genes (289). Two polymorphisms in the PPARD gene were associated with changes in fasting insulin and insulin sensitivity, whereas no association was found with the PPARGC1A gene. The associations between three polymorphisms in the 4.5 LIM domain 1 (FHL1) gene and insulin responses to endurance training were investigated in participants from the HERITAGE Family Study (298). In white men (n = 221), two polymorphisms in the FHL1 gene were associated with fasting insulin, the disposition index and the glucose disappearance index responses to exercise training. In white women (n = 207), one polymorphism was associated with the glucose disappearance index training response. In the study of de Luis et al. (47) described in the Response to exercise section, significant improvements of glucose levels and insulin sensitivity in response to the lifestyle modification program were reported in subjects with the ADRB3 Trp64Trp genotype compared with no improvements in carriers of the Arg64 allele. However, as explained above, in the absence of a statistical test showing a difference between the two genotype groups, we treated this result as a negative finding.
No new linkage studies were published in 2006-2007 (Table 13).
Blood Lipid and Lipoprotein Phenotypes
A total of six new articles were published in 2006/2007 that analyzed genetic association or linkage for lipid responses to acute or chronic exercise and/or PA (Table 14). Seip et al. (276) investigated the effect of APOE genotype on lipoprotein subclass concentrations in response to 6 months of submaximal aerobic exercise training. LDL particle fractions changed significantly after exercise training as a function of genotype, with medium LDL cholesterol (LDL-C) increasing in APOE3/3 homozygotes and decreasing significantly differently from the APOE3/3 genotype class (P < 0.01) in individuals with APOE2/3 or APOE3/4 genotypes. Conversely, small LDL-C increased in APOE2/3 and APOE3/4 heterozygotes and decreased in subjects with the APOE3/3 genotype class, which was significantly different from APOE2/3 and APOE3/4. Although other lipid fractions (all VLDL fractions, large LDL, and small and large HDL) were altered by exercise training, these alterations were not different by APOE genotype (276). In a separate intervention study, participants underwent a lifestyle modification program that consisted of a hypocaloric diet combined with aerobic exercise three times per week for 12 wk (46). Levels of LDL-C were significantly lower by genotype at the Ala54Thr variant in the FABP2 gene after the intervention. Ala54/Ala54 homozygotes had significantly lower LDL levels after exercise/diet intervention, whereas no significant differences were observed in carriers of the Thr54 allele (46).
Hautala et al. (99) investigated two variants (exon 4 + 15 C/T and exon 7 + 65 A/G) in the PPARD gene for associations with blood lipid responses to 20 wk of aerobic exercise training in white and black men and women from the HERITAGE Family Study. In white subjects, both variants were associated with increases in HDL cholesterol (HDL-C) and HDL-C subfractions (HDL2-C and HDL3-C), with exon 4 + 15 C homozygotes and exon 7 + 65 G homozygotes experiencing the largest increases in HDL-C after exercise training. Haplotypes of the two variants were also associated with HDL-C and HDL2-C training response in white subjects (99). In black subjects, HDL-C fractions were not different by genotype, but increases in ApoA1 levels after exercise training were associated with the exon 4 + 15 C/T (but not the exon 7 +65 A/G) polymorphism, with C/C homozygotes having the largest increases in this measure (99). In a separate study of the HERITAGE participants, changes in total HDL-C, HDL-C subfractions, and ApoA1 levels after exercise training were investigated for associations with multiple variants in the CETP gene (286). None of the variants were robustly associated with alterations in blood lipids after exercise training in black subjects. Nevertheless, the −1337C > T and −629C > A variants were both associated with changes in HDL3-C and ApoA1 but only in whites (286). A significant Sex × Genotype interaction was observed for the −629C > A polymorphism for HDL3-C and ApoA1 training response levels. Women with the A/A genotype had significantly higher levels of HDL3-C and ApoA1 after exercise training, whereas no differences in levels of either variable by −629C > A genotype were observed for men (286).
In investigating gene-exercise interactions, Naito et al. (191) reported a significant interaction (P < 0.05) between exercise frequency and genotype for the PPARA V227A polymorphism in predicting HDL-C. Homozygotes for the V227 allele who exercised more than three times per week had significantly higher HDL-C compared with those who exercised two or fewer times per week. No significant differences were observed for HDL-C between exercise frequency groups for the A227 carriers (191).
Only one investigation provided linkage data relevant to blood lipid phenotypes. Feitosa et al. (66) performed a linkage analysis in 99 white and 101 black families, with 654 markers covering the human genome. Significant linkage was observed on chromosome 12q23-q24 for baseline values of HDL-C and TG in white families but not in black families. Weak but nonsignificant signals for HDL-C after exercise training were found for whites but not for blacks (66).
Hemostatic Factors, Inflammation Phenotypes, and Plasma Hormone Levels
One association study investigated the effect of the TNFA G308A polymorphism on levels of C-reactive protein (CRP) before and after a 20-wk exercise intervention in 456 white and 232 black men and women (147). Both black and white men and black women who were homozygous for the 308A allele had significantly higher baseline levels of CRP than carriers of the 308G allele. After exercise training, the significant association between the TNFA G308A variant and the CRP levels remained in white men and black women only, with 308A/308A homozygotes again having the highest levels of CRP compared with other genotypes (147).
Fourteen studies related to exercise intolerance were published in 2006-2007 (Table 15). Seven of the studies reported mutations in six nuclear genes, whereas another seven studies dealt with four mitochondrial genes. Wang et al. (336) investigated a cohort of 44 women diagnosed with Fabry disease. A total of 23 missense and 18 nonsense mutations in the alpha galactosidase (GLA) gene were detected, and 83% of the women were affected by exercise intolerance (336). Gempel et al. (80) reported seven isolated myopathic coenzyme Q10 deficiency patients, who also exhibited exercise intolerance. Other symptoms included fatigue, proximal myopathy, and high serum creatine kinase levels. Mutation screening of electron-transferring flavoprotein dehydrogenase (ETFDH) gene revealed four missense mutations (80).
Kollberg et al. (139) reported three siblings with major skeletal muscle and heart glycogen deficiencies. The two oldest siblings also exhibited exercise intolerance that manifested as difficulty to keep up with physical activities of other children. However, there were no muscle cramps or pain after exercise. Resequencing of the muscle glycogen synthase (GYS1) gene revealed that all three siblings were homozygotes for a mutation in exon 11, which replaced an arginine residue with a premature stop codon at residue 462 (139). Two studies reported mutation screening of the muscle glycogen phosphorylase (PYGM) gene in McArdle disease patients. Rubio et al. (260) reported three patients who were compound heterozygotes of a known Arg50Stop mutation and a novel c.13_14delCT mutation in exon 1. The new exon 1 mutation induces a frameshift and a premature stop codon 21 amino acids downstream from the mutation site. Bruno et al. (26) identified 30 PYGM mutations in 68 Italian McArdle disease patients, including 19 novel variants. However, none of the novel mutations correlated directly with the clinical phenotype of the patients.
Exercise-induced hyperinsulinism (EIHI) is a dominantly inherited disorder that features a paradoxical increase in insulin secretion during anaerobic exercise resulting in hypoglycemia. Otonkoski et al. (205) mapped a QTL for EIHI on chromosome 1 (LOD = 3.6) in two families with 10 EIHI patients. The strongest candidate gene located under the linkage peak was SLC16A1, which encodes monocarboxylate transporter 1. Mutation screening of SLC16A1 revealed promoter mutations in all investigated EIHI patients. Functional studies revealed that the promoter mutations induced a marked transcriptional stimulation of the gene in pancreatic beta cells, where SLC16A1 expression is normally very low. When lactate and pyruvate levels increase during exercise, the abnormally high expression of SLC16A1 in EIHI patients facilitates pyruvate uptake in beta cells and leads to pyruvate-stimulated insulin release although blood glucose level is normal or even low. Finally, Liang et al. (154) reported a novel mutation in codon 520 of the lamin A/C (LMNA) gene in an exercise intolerance patient diagnosed with Emery-Dreifuss muscular dystrophy.
Seven studies reported mutations in four mitochondrial genes in exercise intolerance patients. Additional exercise intolerance patients were reported with a 3243A > G mutation in the MTTL1 locus (316) and novel mutations in the MTTK (19,76) and the MTTE loci (169,207). A new mitochondrial gene entry to the fitness gene map is MTTF that encodes phenylalanine transfer RNA. Darin et al. (43) reported an MTTF 583G > A mutation in a 17-yr-old girl with mitochondrial myopathy and exercise intolerance, whereas a 622G > A mutation was identified in a 66-yr-old woman with a late-onset neuromuscular disease and exercise intolerance (58).
During 2006 and 2007, three studies dealing with DNA sequence variation and PA-related traits were published (Table 16). Richert et al. (245) investigated associations between Gln223Arg polymorphism in the leptin receptor (LEPR) gene and total PA in 222 prepubertal boys. PA level was assessed twice, first at the age of 7 yr and a second time 2 yr later when boys were 9 yr old. Activity level was assessed using questionnaires, and total activity was expressed as PA energy expenditure. The LEPR Arg223Arg homozygotes had a significantly lower PA level than the other two genotypes at baseline (7 yr old), but the difference had disappeared 2 yr later (245).
Cai et al. (30) performed a genome-wide linkage scan for PA phenotypes in 1030 Hispanic children (average age = 11.0 yr) from 319 families. The maximal heritabilities for total PA, sedentary activity, and light and moderate activities (derived from 3-d accelerometer recordings) varied from 46% to 57%. The linkage analysis revealed QTL on chromosome 18q12.2-q21.1 for sedentary and light activities with logarithm of odds (LOD) scores of 4.07 and 2.79, respectively. Maximum LOD scores of 2.28 and 2.2 for total and moderate activities, respectively, were detected about 20 cM downstream at 18q21.32, near the melanocortin 4 receptor (MC4R) locus.
A genome-wide linkage scan for participation in competitive sports was performed in 700 female dizygotic twins (50). Participation history (athlete status) was obtained by asking if the subjects had ever participated in competitive sports and at what level they had competed. A heritability estimate of 66% was derived for athlete status. The genome-wide linkage scan using 1946 markers (736 microsatellites, 1210 SNP) revealed two suggestive QTL on chromosomes 3q22-q24 (LOD = 2.35) and 4q31-q34 (LOD = 1.87) (50).
SUMMARY AND CONCLUSIONS
In this current version of the performance and health-related fitness gene map, we report 27 new autosomal or X-linked genes, one mitochondrial variant, and 24 QTL identified as being associated with fitness or performance traits or exhibiting gene-PA or gene-exercise training interactions since the previous version of the map. A total of 221 autosomal and X-linked genes and 18 mitochondrial markers have been shown to be associated with a relevant phenotype in at least one study, whereas 119 QTL have been reported for exercise- or PA-related traits. Table 17 provides an overview of the evolution of the interest in genetics of fitness and performance traits by family of phenotypes or endophenotypes since the first version of the map in 2000. The ACE gene continues to be by far the most extensively studied of any gene, with at least 58 articles examining the effect of an insertion/deletion polymorphism on fitness and performance traits. The conflicting findings among the many studies for the ACE gene exemplify the complexity of genetic studies of complex traits. Indeed despite the enormous amount of attention that the ACE gene has received, it is still not possible to conclude with certainty whether the common polymorphism in ACE is truly involved in human variation in fitness and performance phenotypes and their response to regular exercise. This is primarily, but not exclusively, due to the fact that studies are almost universally underpowered and because an unknown number of negative studies remain unpublished. In addition to ACE, several other genes are characterized by at least five positive findings; they are ADRB2 (17 studies), VDR (15 articles), APOE (9 studies), MTCYB (9 studies), NOS3 (9 studies), PPARG (6 studies), and ACTN3, ADRB1, AGT, AMPD1, BDKRB2, CPT2, and IGF1 each with five positive articles.
Although the fitness and performance gene map is exhaustive for published accounts in four languages, many other genes have not been investigated yet for their potential contributions to human variation in fitness or performance or trainability. The role of regular PA in reducing the risk for common, chronic diseases such as CV disease, type 2 diabetes, or obesity is generally considered as well established, but the interactions between the specific genes and the benefits accrued from a physically active lifestyle in terms of health outcomes have not received much attention thus far. The same is true for the individual differences in the risk level associated with a sedentary lifestyle. We do not know whether specific genes confer a higher risk or conversely some protection from being chronically sedentary and inactive. Addressing the latter questions is extremely important if we are going to make progress in our understanding of the true role of regular exercise or PA in the prevention of common chronic disease and of physical inactivity in the risk of premature death. Much research is also needed on the genetic basis of a sedentary lifestyle and on the propensity to engage in regular PA. For such a research enterprise to be successful, it is of the utmost importance that it be of very high quality, a requirement that can be attained only through data sharing, collaborative effort, and multicenter studies.
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