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The Human Gene Map for Performance and Health-Related Fitness Phenotypes: The 2003 Update

RANKINEN, TUOMO1; PÉRUSSE, LOUIS2; RAURAMAA, RAINER3; RIVERA, MIGUEL A.4; WOLFARTH, BERND5; BOUCHARD, CLAUDE,1

Medicine & Science in Sports & Exercise: September 2004 - Volume 36 - Issue 9 - p 1451-1469
doi: 10.1249/01.MSS.0000139902.42385.5F
SPECIAL REPORT

RANKINEN, T., L. PÉRUSSE, R. RAURAMAA, M. A. RIVERA, B. WOLFARTH, and C. BOUCHARD. The Human Gene Map for Performance and Health-Related Fitness Phenotypes: The 2003 Update. Med. Sci. Sports Exerc., Vol. 36, No. 9, pp. 1451–1469, 2004. This review presents the 2003 update of the human gene map for physical performance and health-related fitness phenotypes. It is based on peer-reviewed papers published by the end of 2003 and includes association studies with candidate genes, genome-wide scans with polymorphic markers, and single-gene defects causing exercise intolerance to variable degrees. The genes and markers with evidence of association or linkage with a performance or fitness phenotype in sedentary or active people, in adaptation to acute exercise, or for training-induced changes are positioned on the genetic map of all autosomes and the X chromosome. Negative studies are reviewed but a gene or locus must be supported by at least one positive study before being inserted on the map. By the end of 2000, 29 loci were depicted on the first edition of the map. In contrast, the 2003 human gene map for physical performance and health-related phenotypes includes 109 autosomal gene entries and QTL, plus two on the X chromosome. Moreover, there are 15 mitochondrial genes in which sequence variants have been shown to influence relevant fitness and performance phenotypes.

1 Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA; 2 Division of Kinesiology, Department of Preventive Medicine Laval University, SteFoy, Québec, CANADA; 3 Kuopio Research Institute of Exercise Medicine, Department of Physiology, University of Kuopio and Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, FINLAND; 4 Department of Physiology and Department of Physical Medicine, University of Puerto Rico School of Medicine, San Juan, PUERTO RICO; and 5 Department of Preventive and Rehabilitative Sports Medicine, Technical University Munich, Munich, GERMANY

Address for correspondence: Tuomo Rankinen, Ph.D., Pennington Biomedical Research Center Human Genomics Laboratory 6400 Perkins Road Baton Rouge, LA 70808-4124; E-mail: rankint@pbrc.edu.

Submitted for publication April 2004.

Accepted for publication June 2004.

This paper constitutes the fourth installment in the series on the human gene map for performance and health-related fitness phenotypes published in this journal. It covers the peer-reviewed literature published by the end of December 2003. The search for relevant publications is primarily based on the journals 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, training, genotype, polymorphism, mutation, linkage). Other sources include personal reprint collections of the authors and documents made available to us by colleagues who are publishing in this field. The 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 review. 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.

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 retained are grouped under the following categories: hemodynamic traits including exercise heart rate, blood pressure, and heart morphology; anthropometry and body composition; insulin and glucose metabolism; and blood lipid, lipoprotein, and hemostatic factors. Here, we are not concerned by 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. The studies incorporated in the review are fully referenced so that the interested reader can access the original papers. Of interest to some could be the early observations made on athletes, particularly Olympic athletes. The results of these case-control studies based on common red blood cell 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 (119).

Figure 1 depicts the 2003 synthesis of the human performance and health-related fitness gene map for the autosomes and the X chromosome. The 2003 version includes 19 additional gene entries and quantitative trait loci (QTL) and markers as compared with the 2002 version (107). We have also depicted in Figure 2 the gene loci in the mitochondrial DNA in which sequence variants 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.

TABLE 1

TABLE 1

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

TABLE 3

TABLE 3

TABLE 14

TABLE 14

Our goal is to make this publication a useful resource for those who have to teach the role of the inheritance on fitness and performance traits, and the impact of genetic variation among human beings. It is our hope that the yearly update of the fitness and performance gene map is found useful to the exercise scientists and the sports medicine community.

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PERFORMANCE PHENOTYPES

Endurance Phenotypes

Case-control studies.

The case-control studies reporting statistically significant differences in allele and genotype frequencies between endurance athletes and sedentary controls are summarized in Table 2. Yang and coworkers (181) investigated the frequency of a common nonsense mutation in the skeletal muscle alpha 3 actinin (ACTN3) gene in a cohort of 429 international class athletes representing 14 different sports and 436 unrelated controls. In 107 elite sprint and power athletes, they found a significantly lower frequency of the XX genotype (homozygotes for the stop-codon allele) as compared with the controls. In addition, they found the allele frequencies in sprint and endurance athletes deviating in opposite directions with significantly different values between the sprint and endurance groups for male and female athletes, respectively.

TABLE 2

TABLE 2

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Cross-sectional association studies.

Significant results from nine cross-sectional association studies with sequence variations in six different genes were published in 2003 (Table 3). In 400 white subjects from the HERITAGE Family Study, an association was found between the rating of perceived exertion (RPE) during a submaximal-to-maximal exercise test and a C/T transition in the gene encoding the adenosine monophosphate deaminase (AMPD1). In the sedentary state, homozygotes for the rare T allele, which results in a truncated gene product, reported significantly higher RPE during steady-state submaximal exercise at 50 W than the C/C homozygotes and the C/T heterozygotes (129). Franks et al. (33) investigated the associations between a Gly482Ser polymorphism of the peroxisome proliferative activated receptor gamma coactivator 1 alpha (PPARGC1A) gene and physical activity energy expenditure (PAEE) and V̇O2max. PAEE was measured using a 4-d heart rate monitoring and individual resting and exercise oxygen consumption-heart rate relationship, whereas the V̇O2max was predicted from the heart rate and oxygen consumption data measured during submaximal exercise test. Neither PAEE nor predicted V̇O 2max per se was associated with the PPARGC1A polymorphism. However, the correlation between PAEE and predicted V̇O 2max was stronger among the Ser482Ser homozygotes than in the carriers of the 482Gly allele.

Prior and coworkers (111) screened the hypoxia-inducible factor 1alpha (HIF1A) gene for DNA sequence variations and investigated the associations between V̇O 2 max and the HIF1A polymorphisms. One of the novel polymorphisms, an A/T transversion on the 5′-untranslated region of the gene, was associated with V̇O 2max in African-American subjects (marker was not polymorphic in whites): carriers of the T allele showed lower V̇O 2max values than the A/A homozygotes. A total of five studies investigated the angiotensin-converting enzyme (ACE) insertion(I)/deletion(D) polymorphism in cross-sectional studies. Kanazawa and coworkers (61,62) found an association between postexercise lactate values in chronic obstructive pulmonary disease (COPD) patients, with the lowest lactate levels observed in the I/I subjects. Associations between the ACE I/D polymorphism and cardiorespiratory fitness phenotypes measured in normoxic and hypoxic conditions were investigated in healthy, young adults. The ACE I/D genotype was not associated with oxygen consumption at maximal or submaximal exercise. However, hypoxia-induced rise in minute ventilation during submaximal exercise was greater in the I/I homozygotes than in the heterozygotes and the D/D homozygotes (106). In a study with 67 Chinese males, the D allele of the ACE I/D polymorphism was associated with higher levels of V̇O 2max (183). The ACE I/D genotype was not associated with V̇O 2max and several other measurements of exercise capacity in patients with ischemic chronic heart failure (2).

A G/C polymorphism in the promoter region (−174 bp) of the interleukin-6 (IL6) gene was associated with maximal physical working capacity in a large cohort of young, healthy, male smokers. The C/C homozygotes showed significantly lower PWCmax than the heterozygotes and the G allele homozygotes. Among the nonsmokers PWCmax was almost identical across the IL6 genotypes, suggesting that smoking status may modify the association between maximal physical working capacity and the IL6 genotype (104). Exercise-induced decrease in FEV1 was associated with a polymorphism in the secretoglobin, family 1A, member 1 gene (SCGB1A1, a.k.a. uteroglobin) in allergic, asthmatic children (145).

No association was seen between endothelial nitric oxide synthase (NOS3) T-786C genotype and V̇O 2max in trained and untrained females (25). In a small cohort of obese women, V̇O 2max did not differ between the Glu27Glu and Gln27Gln homozygotes of the beta2-adrenergic receptor (ADRB2) gene (82). A loss-of-function polymorphism of the presynaptic alpha2C-adrenergic receptor (ADRA2C) was investigated in 39 patients with idiopathic dilated cardiomyopathy. There was no significant difference between carriers and noncarriers of the 4 aminoacid deletion in the ADRA2C gene, when compared for V̇O 2max or maximum exercise time in an exercise test (41).

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Association studies with training response phenotypes.

Association between the AMPD1 C34T genotype and changes in V̇O 2max before and after a 20-wk controlled endurance-training program was investigated in 400 white subjects of the HERITAGE Family Study. Endurance training-induced increase in oxygen uptake, ventilation, and carbon dioxide production at maximal exercise were significantly lower in T/T homozygotes of the AMPD1 gene polymorphism as compared with C/T and C/C genotypes (129). After 24 wk of aerobic exercise training, an age-by-HIF1A P582S genotype interaction was observed on V̇O 2max training response in Caucasian subjects, with the carriers of the 582S allele showing significantly lower V̇O 2max changes than the P582P homozygotes in the age groups of 60 and 65 yr. However, the V̇O 2max training responses did not differ between the genotypes in 55-yr-old subjects. The authors concluded that the tested HIF1A polymorphism is associated with V̇O 2max before and after aerobic exercise training in older humans (111). The same group reported no association between V̇O 2max response to 24 wk of supervised endurance training and an endothelial lipase gene (LIPG) polymorphism in 83 subjects (51). Frederiksen and coworkers (34) investigated the effects of exercise training on physical functioning and cardiorespiratory fitness in elderly Danes. V̇O 2max improved significantly in the training group as compared to the controls, however the training responses were not associated with the ACE I/D polymorphism.

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Linkage studies.

Linkage studies dealing with endurance phenotypes are summarized in Table 4. No new linkage studies on performance-related phenotypes were published in 2003.

TABLE 4

TABLE 4

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Muscle Strength Phenotypes

The studies reporting associations between strength or anaerobic performance phenotypes with different candidate genes are summarized in Table 5. In 2003, four studies reported data related to strength phenotypes. In the Baltimore Longitudinal Study on Aging cohort, a C174T polymorphism in the ciliary neurotrophic factor receptor (CNTFR) gene was associated with age, race, height, and physical activity-adjusted eccentric slow- and fast-velocity knee extensor peak torque both in men and in women. Carriers of the 174T allele also had a greater nonosseous total and lower limb fat-free mass as compared with the C174C homozygotes. Consequently, the associations between the CNTFR genotype and knee extensor peak torque phenotypes disappeared after further adjustment for fat-free mass, suggesting that the genotype-related differences in lower-limb strength were explained by the differences in muscle mass (135). Frederiksen and coworkers (35) found no associations between ACE I/D genotype and several measured and self-reported strength abilities in elderly Danish twins. In addition, in elderly men aged 71–86 yr, a (TTTA)n-repeat polymorphism in the aromatase enzyme gene (CYP19A1) showed no association with grip strength (166). Likewise, an IL6 C-174G polymorphism was not associated with grip strength or leg extension strength in elderly Italian subjects (8).

TABLE 5

TABLE 5

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HEALTH-RELATED FITNESS PHENOTYPES

Hemodynamic Phenotypes

Acute exercise.

During 2003, two studies reported significant associations between hemodynamic traits measured during acute exercise and candidate gene polymorphisms (Table 6). Kanazawa and coworkers (61,62) reported two studies on the associations between pulmonary hemodynamics during exercise and the ACE I/D polymorphism in patients with COPD. One study investigated the effects of ACE inhibitor captopril on pulmonary arterial pressure and pulmonary vascular resistance (61), whereas the other study addressed the impact of supplementary oxygen administration on the same traits (62). In both reports, the D/D homozygotes showed significantly higher pulmonary artery pressure and pulmonary vascular resistance after acute exercise than patients with one or two copies of the I allele. The ACE I/D polymorphism was not associated with maximal exercise heart rate in patients with chronic ischemic heart failure (2).

TABLE 6

TABLE 6

In the HERITAGE Family Study cohort, a C/T transition at nucleotide +34 of the AMPD1 gene was associated with maximal exercise systolic blood pressure and heart rate. The TT homozygotes showed significantly lower maximal SBP and HR than the heterozygotes and the CC homozygotes (129). The Arg389Gly polymorphism of the beta-1 adrenergic receptor gene (ADRB1) was not associated with heart rate or blood pressure responses to submaximal exercise (149). Likewise, blood pressure and heart rate during two submaximal exercise intensities did not differ among the angiotensinogen (AGT) M235T genotypes in a large cohort of healthy German Air Force pilots (103).

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Gene–physical activity interactions.

The number of studies addressing the question of genotype—fitness and genotype—physical activity interactions on health-related fitness phenotypes has increased, and in 2003, two studies were published dealing with hemodynamic phenotypes (Table 6). Data and coworkers (25) measured resting heart rate and blood pressures as well as forearm blood flow before and after arm arterial occlusion in healthy sedentary and endurance-trained women. Statistically significant interactions were observed between physical activity status and the NOS3 T-786C polymorphism on baseline forearm blood flow (FBF; P = 0.03 for interaction) and forearm vascular resistance (FVR; P = 0.0003 for interaction). Among the sedentary women, the carriers of the −786C allele had lower baseline FBF and higher FVR as compared with the TT homozygotes, whereas in physically active women the TT homozygotes showed lower FBF and higher FVR (25).

In a cohort of 832 healthy middle-aged Japanese subjects, Kimura et al. (68) reported a significant interaction (P = 0.0062) between physical activity status and a 27-bp variable tandem repeat polymorphism located in the intron 4 of the NOS3 gene on resting SBP. Carriers of an allele representing four repeats showed 8.9 mm Hg higher resting SBP than the homozygotes for a 5-repeat allele among the sedentary subjects, whereas no differences were observed between the NOS3 genotypes in the physically active subjects.

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Training response.

The effects of exercise training on acetylcholine-induced changes in average peak velocity (APV) of coronary or mammary arteries was investigated in 67 patients with coronary artery disease (Table 7). Exercise training improved significantly APV. However, the training response was significantly blunted in the carriers of the NOS3 −786C allele as compared to the patients who were homozygotes for the −786T allele (30). In the HERITAGE Family Study, training-induced changes in maximal exercise diastolic blood pressure was associated with the AMPD1 C34T polymorphism: the CC homozygotes showed a greater reduction in maximal DBP than the TT homozygotes (129). Resting blood pressure responses to endurance training did not differ between the PPARG Pro12Ala genotypes in healthy Japanese males (57).

TABLE 7

TABLE 7

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Linkage studies.

In 2003, the first follow-up study of a quantitative trait locus (QTL) from the HERITAGE Family Study was published (120). A QTL for submaximal exercise stroke volume and cardiac output training responses on chromosome 2q31–q32 was investigated further by dense microsatellite mapping (Table 8). The evidence of linkage was greatly enhanced with additional markers and the maximum linkage was detected with markers in or near the gene encoding titin (TTN). Transmission disequilibrium test with the same dense microsatellite marker set provided evidence of association with one of the markers in the TTN gene (120).

TABLE 8

TABLE 8

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Exercise and familial cardiac arrhythmias.

No new genes or mutations were reported in 2003.

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Anthropometry and Body Composition Phenotypes

Association studies.

A total of five studies reported associations between candidate genes and phenotypes related to anthropometry and/or body composition in 2003 (Table 9). All these studies were intervention studies that include exercise as a modality of the intervention; two of these studies dealt with bone-related phenotypes.

TABLE 9

TABLE 9

The first study related to bone phenotypes investigated the relationship between a G-174C polymorphism in the promotor of the IL6 gene and exercise-induced femoral cortical bone resorption in 130 young (19.5 ± 0.2 yr) male army recruits (28). The subjects underwent a 10-wk exercise-training program comprising a mixture of upper- and lower-body strength-endurance exercise of graded workload. Exercise-induced changes in proximal right femoral cross-sectional cortical area, after adjustment for pretraining values, were strongly genotype-dependent with the GG homozygotes losing 6.8% cortical area, GC gaining 5.5% and CC gaining 17.3% (P = 0.007 for linear trend). These genotype-mediated changes persisted throughout the different scans of the femur but were less important in the distal area. The authors concluded that the IL6 gene was an important regulator of the bone remodeling in humans (28).

The second study investigated associations between polymorphisms of the androgen receptor (AR), CYP19A1 and estrogen receptor 1 (ESR1) genes and bone mineral density (BMD) measured in 140 middle-aged Finnish men participating in a 4-yr randomized controlled exercise intervention trial (126). The men in the intervention group (N = 70) were prescribed aerobic exercise, 45–60 min per session, five times a week, whereas the men in the reference group were advised to make their personal choice as to whether or not engage in physical exercise. The lumbar spine BMD values were significantly different among the ESR1 genotypes in the exercise group (P = 0.007), with no significant changes observed in subjects homozygotes (pp) for the mutation (two copies of the PvuII restriction site), whereas increases of 6% and 5%, were observed in subjects with the PP and Pp genotypes, respectively. There were no associations between the AR and CYP19A1 polymorphisms and the BMD responses to the intervention (126).

Three studies reported associations between candidate genes and body fat phenotypes in response to exercise. The effects of the Arg16Gly and Gln27Glu polymorphisms of the ADRB2 gene on various adiposity phenotypes in response to a 20-wk endurance training program was investigated in 482 white and 260 black subjects of the HERITAGE Family Study (39). Associations with the two ADRB2 polymorphisms were tested separately in each of the four race-by-gender groups. No evidence of association with any of the response phenotypes was observed in black subjects. However, endurance training resulted in greater reductions of BMI (P = 0.04), fat mass (P = 0.0008), and percent body fat (P = 0.0003) in white women with the Arg16Arg genotype compared to the Gly16Gly women. The Arg16Gly polymorphism was also associated with changes in subcutaneous fat (P = 0.03) in white men. Moreover, obese men (BMI ≥ 30 kg·m−2) with the Glu27Glu genotype lost, on average, greater amount (P = 0.01) of body fat (−2.79 kg) than obese men with the Gln27Gln genotype (+0.19 kg) (39).

A second study investigated the impact of the Trp64Arg polymorphism of the ADRB3 gene on obesity-related phenotypes in response to a 3-month behavioral intervention using a combination of diet and exercise programs (148). A total of 76 middle-aged (54.3 ± 7.9 yr) women with an average BMI of 24.5 ± 2.1 kg·m−2 underwent a 3-month behavioral weight-loss program including diet, exercise and supportive group therapy. Daily physical activity level was monitored throughout the program using pedometers. The intervention resulted in a significant increase of 52% in the number of steps per day as well as in a significant reduction of body weight, BMI, and waist circumference. However, there were significant differences in the response to the intervention between carriers and noncarriers of the ADRB3 Arg64 allele. The intervention yielded to a reduction of body weight in 48% of the women carrying the Arg64 allele as compared with 69% for the noncarrier women. Changes in body weight (P = 0.001), BMI (P = 0.002), and waist circumference (P = 0.02) were significant only in wild type (Trp64Trp) women. Multiple regression analyses revealed that the Trp64Arg ADRB3 polymorphism was associated with weight loss independently of changes in energy intake and changes in the number steps only in wild type women. The authors concluded that the Trp64Arg mutation of the ADRB3 gene is associated with difficulty in losing weight through behavioral intervention (148).

The third study was aimed at investigating the impact of a polymorphism in the phenylethanolamine N-methyltransferase (PNMT) gene on weight loss induced by a combination of pharmacological treatment (sibutramine) and monthly health-education classes (108). The PNMT gene encodes the rate-limiting enzyme of the conversion of nor-epinephrine to epinephrine and is thus considered as a candidate gene of sibutramine-induced weight loss because this drug acts as an inhibitor of the reuptake of norepinephrine in the neurons. In that study, 149 obese women participated in a 6-month weight loss trial that included daily intake of a dose of 15 mg of sibutramine and a monthly 1-h behavior modification seminar that encouraged participants to eat low-fat foods, increase the consumption of vegetables and fruits, and to exercise daily. Estimates of physical activity were obtained from self-reported daily activity records. A G to A transition in the promotor (position −148) of the PNMT gene was genotyped and tested for association with the response to the intervention. A comparison of the genetic distribution of the G-148A PNMT genotypes between subjects categorized into tertitles of percentage weight loss revealed a significant (P < 0.002) association with greater weight loss in the A/A and G/G homozygotes as compared to the heterozygote G/A subjects. A regression model that included PNMT homozygosity versus heterozygosity and dietary and physical activity variables revealed that the PNMT gene, in addition to total caloric, fat, and fiber intakes, was a significant predictor of percentage of weight loss at 6 months.

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Linkage studies.

The results from linkage studies are shown in Table 10. There were no linkage studies pertaining to the response of body composition phenotypes to exercise that were published in 2003.

TABLE 10

TABLE 10

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Insulin and Glucose Metabolism Phenotypes.

Table 11 presents the results for insulin and glucose metabolism phenotypes. A new table describing results from these phenotypes was added in this year’s version of the map as there are now six studies that have reported associations with insulin or glucose metabolism phenotypes. Three were described in the previous maps (27,58,137) and three new studies were published in 2003. In one of these new studies, the Gln27Glu ADRB2 polymorphism was tested for its potential impact on the metabolic response of obese women submitted to a peak oxygen consumption test on treadmill (82). In that study, 10 obese women with the Gln27Gln genotype were compared with 9 obese women with the Glu27Glu genotype matched by age, BMI, percent body fat, and waist circumference. These women were submitted to a maximal multistage exercise treadmill test, and blood samples were collected through a venous catheter at baseline, during the maximal effort and 5 min after completion of the test for measurements of glycerol, triglycerides, glucose, and insulin levels. Results revealed that women with the Glu27Glu genotype had lower plasma glycerol (P = 0.03), higher plasma triglycerides (P < 0.001), and higher values of the insulin to glucose ratio (P = 0.046) than the Gln27Gln women. Lipid oxidation during the recovery period was also found to be lower in the Glu27Glu women compared with the other group of women. These results suggest that obese women with the Glu27Glu genotype are less prone to utilize fat during exercise, which could be associated with reduced insulin sensitivity.

TABLE 11

TABLE 11

In a second study, the Pro12Ala polymorphism in the PPARG gene was investigated for its effects on insulin resistance in response to exercise in 123 healthy Japanese men aged 21–69 yr (57). The exercise program was designed to attain a physical activity level of 700 kcal·wk−1 and consisted mainly of brisk walking at an individual intensity of 50% of maximal heart rate, 20–60 min·d−1, and two to three times per week for a period of 3 months. Several clinical and metabolic characteristics, including fasting plasma glucose and insulin levels, were measured before and after the exercise program. Although there were no associations with the clinical and metabolic characteristics at baseline, the Pro12Ala PPARG polymorphism was significantly associated with changes in fasting insulin (P = 0.02) and the HOMA insulin resistance index (P = 0.05), with improvements in insulin resistance in the heterozygotes (N = 6) compared with the homozygotes for the Pro allele (N = 117).

Finally, the third study investigated the impact of a common vitamin D receptor (VDR) gene polymorphism (BsmI) on fasting serum glucose levels in 1539 active aircrew members of the armed forces (102). The BsmI VDR gene polymorphism was considered because vitamin D modulates insulin receptor gene expression and because of previous associations reported between this polymorphism and Type 2 diabetes. Physical activity was assessed based on the average time per week spent on sports activity over the year, and subjects were categorized into low (≤3 h) and high (>3 h) physical activity groups. The authors found that subjects of the low physical activity group with the BB genotype had higher levels of fasting glucose (5.61 ± 0.49 mmol·L−1) than subjects with the Bb (5.44 ± 0.44 mmol·L−1) or bb (5.38 ± 0.44 mmol·L−1) genotypes (P < 0.001). This association was not observed in subjects within the high physical activity group. The results suggest that the BsmI VDR polymorphism is associated with the control of glucose homeostasis in young men with low physical activity level (102).

The first genome-wide linkage scan for endurance training–induced changes in fasting plasma insulin levels was published in 2003 (76). The strongest evidence of linkage was detected on chromosome 7q31 near the leptin (LEP) gene locus in White HERITAGE Families (Table 12). Suggestive evidence of linkage was also observed on chromosomes 2q31, 7q21 and 11q13 in whites and on chromosome 15p11 in blacks (76).

TABLE 12

TABLE 12

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Blood Lipid, Lipoprotein, and Hemostatic Factor Phenotypes.

Six new studies were published in 2003 related to DNA sequence variation in candidate genes, physical activity, and blood lipids and lipoproteins (Table 13). The acute effect of maximal treadmill exercise on fat oxidation, determined by indirect calorimetry, was measured in obese women with regard to the Gln27Glu polymorphism of the ADRB2 gene (82). Compared with the Gln27Gln group, the Glu27Glu homozygotes showed higher plasma triglyceride levels before, during, and after exercise, as well as a significantly lower fat oxidation during the recovery period.

TABLE 13

TABLE 13

Pisciotta and coworkers (109) investigated associations between apolipoprotein E (APOE), fatty acid binding protein 2 (FABP2), apolipoprotein A-II (APOA2), and LIPC gene polymorphisms and cardiovascular risk factors in sedentary and physically active middle-aged men. APOE genotype was associated with low-density lipoprotein (LDL)-cholesterol and apolipoprotein B levels both in the sedentary and active group. However, elevated LDL-C and apoB levels associated with the APOE epsilon 4 allele were seen only in the sedentary men, whereas in the physically active men the epsilon 2 allele was associated with lower LDL-C and apoB levels. Similarly, plasma triglyceride levels were associated with the APOA2 genotype in sedentary but not in the physically active men. Finally, the homozygotes for the LIPC −250A allele showed higher plasma high-density lipoprotein (HDL)-cholesterol and apolipoprotein A-I levels than the other genotypes in the active group but not in the sedentary subjects (109). No interactions were detected between physical activity and CETP and APOE genotypes on plasma lipid and lipoprotein levels in a large cohort of men and women from Switzerland (9) and in postmenopausal women representing different levels of physical activity (50), respectively. Endurance training-induced changes in plasma HDL cholesterol levels were associated with the LIPG genotype. The C/C homozygotes showed a greater HDL training response than the T allele carriers (51). In middle-aged Japanese men, changes in plasma total and HDL-cholesterol and triglyceride levels brought about by a 3-month exercise-training program did not differ between the PPARG Pro12Ala genotypes (57).

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Chronic Diseases.

The previous three updates of the Human Fitness Gene Map have summarized the available information on several risk factors for chronic diseases. In 2003, the first studies were published on the genotype-physical activity interactions on the actual risk of chronic diseases.

In the San Luis Valley Diabetes Study, 397 Hispanics and 569 non-Hispanic Whites were followed for 14 yr. During the follow-up, 91 coronary heart disease (CHD) events were recorded. The frequency of the T/T genotype of the LIPC C–480T polymorphism was higher among the CHD cases, and the CHD-free survival during the follow-up among the T/T homozygotes was significantly worse than in the C/C homozygotes and the C/T heterozygotes. A multivariate analysis revealed a significant interaction between the LIPC C-480T genotype and physical activity level on the CHD risk. The increased CHD risk associated with the T/T genotype was observed in the sedentary or moderately active subjects but not in subjects who participated in vigorous physical activities (54).

A lifestyle intervention utilizing both dietary and physical activity programs resulted in a significant reduction in the incidence of diabetes in middle-aged, overweight subjects with impaired glucose tolerance (164). A G-308A polymorphism of the tumor necrosis factor (TNF) gene was significantly associated with the risk of developing Type 2 diabetes during the follow-up. Carriers of the −308A allele showed 1.8 times greater risk than the G/G homozygotes. Interestingly, the lower diabetes risk associated with the G/G genotype was seen only in the lifestyle intervention group: the incidence of Type 2 diabetes was 5.0% and 18.2% in the GG homozygotes and the A allele carriers (odds ratio 4.22), respectively, whereas the corresponding values in the control group were 20.8% and 22.7% (72).

King and coworkers (69) investigated the risk of breast and ovarian cancer associated with the mutations in the BRCA1 and BRCA2 genes in Ashkenazi Jewish women. Although mutations in both genes significantly increase the risk of breast cancer, the results suggested that physical activity and body weight might modify the penetrance of the disease. Mutation carriers who were physically active as teenagers were diagnosed with breast cancer significantly later in life (i.e., older age of onset) than did those who were sedentary (69).

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Exercise Intolerance.

In 2003, four studies related to exercise intolerance were published (Table 14). These included one study reporting a new gene for exercise intolerance, two studies showing new causal mutations in already known intolerance gene, and one study reporting associations between physical performance related candidate genes and severity of the symptoms in McArdle’s disease patients.

Grafakou and coworkers (43) identified a mutation in the mitochondrial serine transfer RNA (MTTS1) in a 13-yr-old girl with nonfamilial exercise intolerance. A G/A transition at position 7497 in the MTTS1 gene was found in mitochondrial DNA isolated from patient’s skeletal muscle, where it appeared to be homoplasmic. The mutation was not found in 200 healthy controls (43). Two new nonsense mutations in the mitochondrial cytochrome b (MTCYB) gene were reported in patients exhibiting exercise intolerance (17,84). A G15170A mutation was detected in a 40-yr-old woman with progressive exercise intolerance. The mutation induces a premature stop codon at amino acid position 142 leading to a loss of 238 amino acids of the protein (17). In a 19-yr-old woman with life-long exercise intolerance, a novel G15761A mutation resulting in a stop codon at amino acid position 339 was detected (84). Both MTCYB mutations were very abundant in patients’ skeletal muscle but undetectable in other tissues investigated (17,84).

Martinuzzi and coworkers (86) investigated whether common DNA sequence variants in the AMPD1 and ACE genes are associated with the severity of symptoms in 47 patients with McArdle’s disease. The patients were divided in four categories based on the extent of their symptoms, ranging from mild exercise intolerance to severe limitations in exercise capacity and daily life activities. The genotype frequencies of the AMPD1 C34T polymorphism did not differ between the symptom categories. However, frequency of the ACE D allele was significantly higher among the patients with more severe symptoms. All ten ACE D/D homozygote patients were either in the most severe or the second most severe symptom category. The authors put forward a hypothesis that ACE activity could be one factor contributing to the heterogeneity of the symptoms in the McArdle’s disease patients (86).

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SUMMARY AND CONCLUSIONS

This review provides a compendium of all genes and markers that have been associated with performance and health-related fitness phenotypes in scientific papers published by the end of 2003. Even those who know little about molecular biology realize that exciting advances have been made in the understanding of the molecular and cellular regulation of the adaptation to activity and inactivity in the last decade. Although we have a long way to go, we are beginning to understand which genes and pathways are contributing to the response of various tissues and organs to acute or repeated exposures to exercise or muscle contractions. These studies are of paramount importance if we are to understand the true biological determinants of physical performance and of the role of regular exercise in disease prevention or of physical inactivity in common chronic diseases and premature death.

In contrast, little progress has been made with respect to the genetic basis of human variation in performance and health-related fitness. Indeed the biological basis of human individuality is a very different topic that has received only very limited attention to date. The current stagnation on the genetic front needs to benefit from the advances that are taking place in the molecular and cellular biology of exercise. The focus of these yearly reviews is on the genetic basis of human individuality for relevant traits and biological properties.

The 2003 map includes 109 autosomal entries, 2 X chromosome assignments, and 15 mt DNA markers. There are 19 nuclear genome markers more than in 2002. Given the complexity of the performance and health-related fitness phenotypes, it should be obvious that we have a long way to go before we have a satisfactory understanding of the role of genetic inheritance on exercise related traits and in the adaptation to a physically active lifestyle. As in previous years, we are forced to conclude that advances in this field are registered at a very modest pace.

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REFERENCES

1. Abraham, M. R., L. J. Olson, M. J. Joyner, S. T. Turner, K. C. Beck, and B. D. Johnson. Angiotensin-converting enzyme genotype modulates pulmonary function and exercise capacity in treated patients with congestive stable heart failure. Circulation 106:1794–1799, 2002.
2. Akbulut, T., T. Bilsel, S. Terzi, et al. Relationship between ACE gene polymorphism and ischemic chronic heart failure in Turkish population. Eur. J. Med. Res. 8:247–253, 2003.
3. Alvarez, R., N. Terrados, R. Ortolano, et al. Genetic variation in the renin-angiotensin system and athletic performance. Eur. J. Appl. Physiol. 82:117–120, 2000.
4. Andreu, A. L., C. Bruno, T. C. Dunne, et al. A nonsense mutation (G15059A) in the cytochrome b gene in a patient with exercise intolerance and myoglobinuria. Ann. Neurol. 45:127–130, 1999.
5. Andreu, A. L., C. Bruno, S. Shanske, et al. Missense mutation in the mtDNA cytochrome b gene in a patient with myopathy. Neurology 51:1444–1447, 1998.
6. Andreu, A. L., M. G. Hanna, H. Reichmann, et al. Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N. Engl. J. Med. 341:1037–1044, 1999.
7. Andreu, A. L., K. Tanji, C. Bruno, et al. Exercise intolerance due to a nonsense mutation in the mtDNA ND4 gene. Ann. Neurol. 45:820–823, 1999.
8. Barbieri, M., L. Ferrucci, E. Ragno, et al. Chronic inflammation and the effect of IGF-I on muscle strength and power in older persons. Am. J. Physiol. Endocrinol. Metab. 284:E481–E487, 2003.
9. Bernstein, M. S., M. C. Costanza, R. W. James, et al. No physical activity x CETP 1b.-629 interaction effects on lipid profile. Med. Sci. Sports Exerc. 35:1124–1129, 2003.
10. Bernstein, M. S., M. C. Costanza, R. W. James, et al. Physical activity may modulate effects of ApoE genotype on lipid profile. Arterioscler. Thromb. Vasc. Biol. 22:133–140, 2002.
11. Blanchet, C., Y. Giguere, D. Prud’homme, M. Dumont, F. Rousseau, and S. Dodin. Association of physical activity and bone: influence of vitamin D receptor genotype. Med. Sci. Sports Exerc. 34:24–31, 2002.
12. Boer, J. M., J. A. Kuivenhoven, E. J. Feskens, et al. Physical activity modulates the effect of a lipoprotein lipase mutation (D9N) on plasma lipids and lipoproteins. Clin. Genet. 56:158–163, 1999.
13. Bouchard, C., T. Rankinen, Y. Chagnon, et al. Genomic scan for maximal oxygen uptake and its response to training in the HERITAGE Family Study. J. Appl. Physiol. 88:551–559, 2000.
14. Brull, D., S. Dhamrait, S. Myerson, et al. Bradykinin B2BKR receptor polymorphism and left-ventricular growth response. Lancet 358:1155–1156, 2001.
15. Brull, D. J., S. Dhamrait, R. Moulding, et al. The effect of fibrinogen genotype on fibrinogen levels after strenuous physical exercise. Thromb. Haemost. 87:37–41, 2002.
16. Bruno, C., G. Manfredi, A. L. Andreu, et al. A splice junction mutation in the alpha(M) gene of phosphorylase kinase in a patient with myopathy. Biochem. Biophys. Res. Commun. 249:648–651, 1998.
17. Bruno, C., F. M. Santorelli, S. Assereto, et al. Progressive exercise intolerance associated with a new muscle-restricted nonsense mutation (G142X) in the mitochondrial cytochrome b gene. Muscle Nerve 28:508–511, 2003.
18. Buemann, B., B. Schierning, S. Toubro, et al. The association between the val/ala-55 polymorphism of the uncoupling protein 2 gene and exercise efficiency. Int. J. Obes. Relat. Metab. Disord. 25:467–471, 2001.
19. Campos, Y., J. Bautista, E. Gutierrez-Rivas, et al. Clinical heterogeneity in two pedigrees with the 3243 bp tRNA(Leu(UUR)) mutation of mitochondrial DNA. Acta Neurol. Scand. 91:62–65, 1995.
20. Campos, Y., A. Garcia, A. Lopez, et al. Cosegregation of the mitochondrial DNA A1555G and G4309A mutations results in deafness and mitochondrial myopathy. Muscle Nerve 25:185–188, 2002.
21. Chagnon, Y. C., T. Rice, L. Perusse, et al. Genomic scan for genes affecting body composition before and after training in Caucasians from HERITAGE. J. Appl. Physiol. 90:1777–1787, 2001.
22. Comi, G. P., F. Fortunato, S. Lucchiari, et al. Beta-enolase deficiency, a new metabolic myopathy of distal glycolysis. Ann. Neurol. 50:202–207, 2001.
23. Corbalan, M. S. The 27Glu polymorphism of the beta2-adrenergic receptor gene interacts with physical activity influencing obesity risk among female subjects. Clin. Genet. 61:305–307, 2002.
24. Corella, D., M. Guillen, C. Saiz, et al. Environmental factors modulate the effect of the APOE genetic polymorphism on plasma lipid concentrations: ecogenetic studies in a Mediterranean Spanish population. Metabolism 50:936–944, 2001.
25. Data, S. A., M. H. Roltsch, B. Hand, R. E. Ferrell, J. J. Park, and M. D. Brown. eNOS T-786C genotype, physical activity, and peak forearm blood flow in females. Med. Sci. Sports Exerc. 35:1991–1997, 2003.
26. Delanghe, J., M. Langlois, D. Duprez, M. De Buyzere, and D. Clement. Haptoglobin polymorphism and peripheral arterial occlusive disease. Atherosclerosis 145:287–292, 1999.
27. Dengel, D. R., M. D. Brown, R. E. Ferrell, T. Ht. Reynolds, and M. A. Supiano. Exercise-induced changes in insulin action are associated with ACE gene polymorphisms in older adults. Physiol. Genomics 11:73–80, 2002.
28. Dhamrait, S. S., L. James, D. J. Brull, et al. Cortical bone resorption during exercise is interleukin-6 genotype-dependent. Eur. J. Appl. Physiol. 89:21–25, 2003.
29. Dionne, F. T., L. Turcotte, M. C. Thibault, M. R. Boulay, J. S. Skinner, and C. Bouchard. Mitochondrial DNA sequence polymorphism, VO2max, and response to endurance training. Med. Sci. Sports Exerc. 23:177–185, 1991.
30. Erbs, S., Y. Baither, A. Linke, et al. Promoter but not exon 7 polymorphism of endothelial nitric oxide synthase affects training-induced correction of endothelial dysfunction. Arterioscler. Thromb. Vasc. Biol. 23:1814–1819, 2003.
31. Fatini, C., R. Guazzelli, P. Manetti, et al. RAS genes influence exercise-induced left ventricular hypertrophy: an elite athletes study. Med. Sci. Sports Exerc. 32:1868–1872, 2000.
32. Folland, J., B. Leach, T. Little, et al. Angiotensin-converting enzyme genotype affects the response of human skeletal muscle to functional overload. Exp. Physiol. 85:575–579, 2000.
33. Franks, P. W., I. Barroso, J. Luan, et al. PGC-1alpha genotype modifies the association of volitional energy expenditure with VO2max. Med. Sci. Sports Exerc. 35:1998–2004, 2003.
34. Frederiksen, H., L. Bathum, C. Worm, K. Christensen, and L. Puggaard. ACE genotype and physical training effects: a randomized study among elderly Danes. Aging Clin. Exp Res. 15:284–291, 2003.
35. Frederiksen, H., D. Gaist, L. Bathum, et al. Angiotensin I-converting enzyme (ACE) gene polymorphism in relation to physical performance, cognition and survival–a follow-up study of elderly Danish twins. Ann. Epidemiol. 13:57–65, 2003.
36. Friedl, W., F. Krempler, F. Sandhofer, and B. Paulweber. Insertion/deletion polymorphism in the angiotensin-converting-enzyme gene and blood pressure during ergometry in normal males. Clin. Genet. 50:541–544, 1996.
37. Friedl, W., J. Mair, M. Pichler, B. Paulweber, F. Sandhofer, and B. Puschendorf. Insertion/deletion polymorphism in the angiotensin-converting enzyme gene is associated with atrial natriuretic peptide activity after exercise. Clin. Chim Acta 274:199–211, 1998.
38. Garenc, C., L. Perusse, J. Bergeron, et al. Evidence of LPL gene-exercise interaction for body fat and LPL activity: the HERITAGE Family Study. J. Appl. Physiol. 91:1334–1340, 2001.
39. Garenc, C., L. Perusse, Y. C. Chagnon, et al. Effects of beta2-adrenergic receptor gene variants on adiposity: the HERITAGE Family Study. Obes. Res. 11:612–618, 2003.
40. Gayagay, G., B. Yu, B. Hambly, et al. Elite endurance athletes and the ACE I allele: the role of genes in athletic performance. Hum. Genet. 103:48–50, 1998.
41. Gerson, M. C., L. E. Wagoner, N. McGuire, and S. B. Liggett. Activity of the uptake-1 norepinephrine transporter as measured by I-123 MIBG in heart failure patients with a loss-of-function polymorphism of the presynaptic alpha2C-adrenergic receptor. J. Nucl. Cardiol. 10:583–589, 2003.
42. Geusens, P., C. Vandevyver, J. Vanhoof, J. J. Cassiman, S. Boonen, and J. Raus. Quadriceps and grip strength are related to vitamin D receptor genotype in elderly nonobese women. J. Bone Miner. Res. 12:2082–2088, 1997.
43. Grafakou, O., F. A. Hol, K. Otfried Schwab, et al. Exercise intolerance, muscle pain and lactic acidaemia associated with a 7497G>A mutation in the tRNASer(UCN) gene. J. Inherit. Metab. Dis. 26:593–600, 2003.
44. Grunig, E., B. Janssen, D. Mereles, et al. Abnormal pulmonary artery pressure response in asymptomatic carriers of primary pulmonary hypertension gene. Circulation 102:1145–1150, 2000.
45. Hadjigeorgiou, G. M., N. Kawashima, C. Bruno, et al. Manifesting heterozygotes in a Japanese family with a novel mutation in the muscle-specific phosphoglycerate mutase (PGAM-M) gene. Neuromuscul. Disord. 9:399–402, 1999.
46. Hagberg, J. M., R. E. Ferrell, D. R. Dengel, and K. R. Wilund. Exercise training-induced blood pressure and plasma lipid improvements in hypertensives may be genotype dependent. Hypertension 34:18–23, 1999.
47. Hagberg, J. M., R. E. Ferrell, L. I. Katzel, D. R. Dengel, J. D. Sorkin, and A. P. Goldberg. Apolipoprotein E genotype and exercise training-induced increases in plasma high-density lipoprotein (HDL)- and HDL2-cholesterol levels in overweight men. Metabolism 48:943–945, 1999.
48. Hagberg, J. M., R. E. Ferrell, S. D. McCole, K. R. Wilund, and G. E. Moore. VO2 max is associated with ACE genotype in postmenopausal women. J. Appl. Physiol. 85:1842–1846, 1998.
49. Hagberg, J. M., S. D. McCole, M. D. Brown, et al. ACE insertion/deletion polymorphism and submaximal exercise hemodynamics in postmenopausal women. J. Appl. Physiol. 92:1083–1088, 2002.
50. Hagberg, J. M., S. D. McCole, R. E. Ferrell, et al. Physical activity, hormone replacement therapy and plasma lipoprotein-lipid levels in postmenopausal women. Int. J. Sports Med. 24:22–29, 2003.
51. Halverstadt, A., D. A. Phares, R. E. Ferrell, K. R. Wilund, A. P. Goldberg, and J. M. Hagberg. High-density lipoprotein-cholesterol, its subfractions, and responses to exercise training are dependent on endothelial lipase genotype. Metabolism 52:1505–1511, 2003.
52. Hanna, M. G., I. P. Nelson, S. Rahman, et al. Cytochrome c oxidase deficiency associated with the first stop-codon point mutation in human mtDNA. Am. J. Hum. Genet. 63:29–36, 1998.
53. Hao, H., E. Bonilla, G. Manfredi, S. DiMauro, and C. T. Moraes. Segregation patterns of a novel mutation in the mito-chondrial tRNA glutamic acid gene associated with myopathy and diabetes mellitus. Am. J. Hum. Genet. 56:1017–1025, 1995.
54. Hokanson, J. E., M. I. Kamboh, S. Scarboro, R. H. Eckel, and R. F. Hamman. Effects of the hepatic lipase gene and physical activity on coronary heart disease risk. Am. J. Epidemiol. 158:836–843, 2003.
55. Ivey, F. M., S. M. Roth, R. E. Ferrell, et al. Effects of age, gender, and myostatin genotype on the hypertrophic response to heavy resistance strength training. J. Gerontol. A Biol. Sci. Med. Sci. 55:M641–M648, 2000.
56. Jamshidi, Y., H. E. Montgomery, H. W. Hense, et al. Peroxisome proliferator–activated receptor alpha gene regulates left ventricular growth in response to exercise and hypertension. Circulation 105:950–955, 2002.
57. Kahara, T., T. Takamura, T. Hayakawa, et al. PPARgamma gene polymorphism is associated with exercise-mediated changes of insulin resistance in healthy men. Metabolism 52:209–212, 2003.
58. Kahara, T., T. Takamura, T. Hayakawa, et al. Prediction of exercise-mediated changes in metabolic markers by gene polymorphism. Diabetes Res. Clin. Pract. 57:105–110, 2002.
59. Kallio, J., U. Pesonen, K. Kaipio, et al. Altered intracellular processing and release of neuropeptide Y due to leucine 7 to proline 7 polymorphism in the signal peptide of preproneuropeptide Y in humans. FASEB J. 15:1242–1244, 2001.
60. Kallio, J., U. Pesonen, M. K. Karvonen, et al. Enhanced exercise-induced GH secretion in subjects with Pro7 substitution in the prepro-NPY. J. Clin. Endocrinol Metab. 86:5348–5352, 2001.
61. Kanazawa, H., K. Hirata, and J. Yoshikawa. Effects of captopril administration on pulmonary haemodynamics and tissue oxygenation during exercise in ACE gene subtypes in patients with COPD: a preliminary study. Thorax 58:629–631, 2003.
62. Kanazawa, H., K. Hirata, and J. Yoshikawa. Influence of oxygen administration on pulmonary haemodynamics and tissue oxygenation during exercise in COPD patients with different ACE genotypes. Clin. Physiol. Funct. Imaging 23:332–336, 2003.
63. Kanazawa, H., T. Okamoto, K. Hirata, and J. Yoshikawa. Deletion polymorphisms in the angiotensin converting enzyme gene are associated with pulmonary hypertension evoked by exercise challenge in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 162:1235–1238, 2000.
64. Kanazawa, H., T. Otsuka, K. Hirata, and J. Yoshikawa. Association between the angiotensin-converting enzyme gene polymorphisms and tissue oxygenation during exercise in patients with COPD. Chest 121:697–701, 2002.
65. Karadimas, C. L., P. Greenstein, C. M. Sue, et al. Recurrent myoglobinuria due to a nonsense mutation in the COX I gene of mitochondrial DNA. Neurology 55:644–649, 2000.
66. Karadimas, C. L., L. Salviati, S. Sacconi, et al. Mitochondrial myopathy and ophthalmoplegia in a sporadic patient with the G12315A mutation in mitochondrial DNA. Neuromuscul. Disord. 12:865–868, 2002.
67. Keightley, J. A., R. Anitori, M. D. Burton, F. Quan, N. R. Buist, and N. G. Kennaway. Mitochondrial encephalomyopathy and complex III deficiency associated with a stop-codon mutation in the cytochrome b gene. Am. J. Hum. Genet. 67:1400–1410, 2000.
68. Kimura, T., T. Yokoyama, Y. Matsumura, et al. NOS3 genotype-dependent correlation between blood pressure and physical activity. Hypertension 41:355–360, 2003.
69. King, M. C., J. H. Marks, and J. B. Mandell. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302:643–646, 2003.
70. Kitagawa, I., Y. Kitagawa, T. Nagaya, and S. Tokudome. Interplay of physical activity and vitamin D receptor gene polymorphism on bone mineral density. J. Epidemiol. 11:229–232, 2001.
71. Krizanova, O., J. Koska, M. Vigas, and R. Kvetnansky. Correlation of M235T DNA polymorphism with cardiovascular and endocrine responses during physical exercise in healthy subjects. Physiol. Res. 47:81–88, 1998.
72. Kubaszek, A., J. Pihlajamaki, V.Komarovski, et al. Promoter polymorphisms of the TNF-alpha (G-308A) and IL-6 (C-174G) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study. Diabetes 52:1872–1876, 2003.
73. Lahat, H., M. Eldar, E. Levy-Nissenbaum, et al. Autosomal recessive catecholamine- or exercise-induced polymorphic ventricular tachycardia: clinical features and assignment of the disease gene to chromosome 1p13–21. Circulation 103:2822–2827, 2001.
74. Lahat, H., E. Pras, T. Olender, et al. A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel. Am. J. Hum. Genet. 69:1378–1384, 2001.
75. Laitinen, P. J., K. M. Brown, et al. Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation 103:485–490, 2001.
76. Lakka, T. A., T. Rankinen, S. J. Weisnagel, et al. A quantitative trait locus on 7q31 for the changes in plasma insulin in response to exercise training: the HERITAGE Family Study. Diabetes 52:1583–1587, 2003.
77. Lamantea, E., F. Carrara, C. Mariotti, L. Morandi, V. Tiranti, and M. Zeviani. A novel nonsense mutation (Q352X) in the mitochondrial cytochrome b gene associated with a combined deficiency of complexes I and III. Neuromuscul. Disord. 12:49–52, 2002.
78. Lanouette, C. M., Y. C. Chagnon, T. Rice, et al. Uncoupling protein 3 gene is associated with body composition changes with training in HERITAGE study. J. Appl. Physiol. 92:1111–1118, 2002.
79. Lindi, V. I., M. I. Uusitupa, J. Lindstrom, et al. Association of the Pro12Ala polymorphism in the PPAR-gamma2 gene with 3-year incidence of type 2 diabetes and body weight change in the Finnish Diabetes Prevention Study. Diabetes 51:2581–2586, 2002.
80. Lorentzon, M., R. Lorentzon, and P. Nordstrom. Vitamin D receptor gene polymorphism is related to bone density, circulating osteocalcin, and parathyroid hormone in healthy adolescent girls. J. Bone Miner. Metab. 19:302–307, 2001.
81. Macho-Azcarate, T., J. Calabuig, A. Marti, and J. A. Martinez. A maximal effort trial in obese women carrying the beta2-adrenoceptor Gln27Glu polymorphism. J. Physiol. Biochem. 58:103–108, 2002.
82. Macho-Azcarate, T., A. Marti, J. Calabuig, and J. A. Martinez. Basal fat oxidation and after a peak oxygen consumption test in obese women with a beta2 adrenoceptor gene polymorphism. J. Nutr. Biochem. 14:275–279, 2003.
83. Macho-Azcarate, T., A. Marti, A. Gonzalez, J. A. Martinez, and J. Ibanez. Gln27Glu polymorphism in the beta2 adrenergic receptor gene and lipid metabolism during exercise in obese women. Int. J. Obes. Relat. Metab. Disord. 26:1434–1441, 2002.
84. Mancuso, M., M. Filosto, J. C. Stevens, et al. Mitochondrial myopathy and complex III deficiency in a patient with a new stop-codon mutation (G339X) in the cytochrome b gene. J. Neurol. Sci. 209:61–63, 2003.
85. Martin, M. A., J. C. Rubio, P. del Hoyo, et al. Identification of novel mutations in Spanish patients with muscle carnitine palmitoyltransferase II deficiency. Hum. Mutat. 15:579–580, 2000.
86. Martinuzzi, A., E. Sartori, M. Fanin, et al. Phenotype modulators in myophosphorylase deficiency. Ann. Neurol. 53:497–502, 2003.
87. McCole, S. D., M. D. Brown, G. E. Moore, et al. Angiotensinogen M235T polymorphism associates with exercise hemodynamics in postmenopausal women. Physiol. Genomics 10:63–69, 2002.
88. Meirhaeghe, A., N. Helbecque, D. Cottel, and P. Amouyel. Beta2-adrenoceptor gene polymorphism, body weight, and physical activity. Lancet 353:896, 1999.
89. Meirhaeghe, A., J. Luan, P. Selberg-Franks, et al. The effect of the Gly16Arg polymorphism of the beta(2)-adrenergic receptor gene on plasma free fatty acid levels is modulated by physical activity. J. Clin. Endocrinol. Metab. 86:5881–5887, 2001.
90. Mongini, T., C. Doriguzzi, I. Bosone, L. Chiado-Piat, E. P. Hoffman, and L. Palmucci. Alpha-sarcoglycan deficiency featuring exercise intolerance and myoglobinuria. Neuropediatrics 33:109–111, 2002.
91. Montgomery, H., P. Clarkson, M. Barnard, et al. Angiotensin-converting-enzyme gene insertion/deletion polymorphism and response to physical training. Lancet 353:541–545, 1999.
92. Montgomery, H. E., P. Clarkson, C. M. Dollery, et al. Association of angiotensin-converting enzyme gene I/D polymorphism with change in left ventricular mass in response to physical training. Circulation 96:741–747, 1997.
93. Montgomery, H. E., P. Clarkson, O. M. Nwose, et al. The acute rise in plasma fibrinogen concentration with exercise is influenced by the G-453-A polymorphism of the beta-fibrinogen gene. Arterioscler. Thromb. Vasc. Biol. 16:386–391, 1996.
94. Montgomery, H. E., R. Marshall, H. Hemingway, et al. Human gene for physical performance. Nature 393:221–222, 1998.
95. Moore, G. E., A. R. Shuldiner, J. M. Zmuda, R. E. Ferrell, S. D. McCole, and J. M. Hagberg. Obesity gene variant and elite endurance performance. Metabolism 50:1391–1392, 2001.
96. Munoz-Malaga, A., J. Bautista, J. A. Salazar, et al. Lipomatosis, proximal myopathy, and the mitochondrial 8344 mutation: a lipid storage myopathy?Muscle Nerve 23:538–542, 2000.
    97. Musumeci, O., A. L. Andreu, S. Shanske, et al. Intragenic Inversion of mtDNA: a new type of pathogenic mutation in a patient with mitochondrial myopathy. Am. J. Hum. Genet. 66:1900–1904, 2000.
    98. Myerson, S., H. Hemingway, R. Budget, J. Martin, S. Humphries, and H. Montgomery. Human angiotensin I-converting enzyme gene and endurance performance. J. Appl. Physiol. 87:1313–1316, 1999.
    99. Myerson, S. G., H. E. Montgomery, M. Whittingham, et al. Left ventricular hypertrophy with exercise and ace gene insertion/deletion polymorphism: a randomized controlled trial with losartan. Circulation 103:226–230, 2001.
    100. Nakamura, O., T. Ishii, Y. Ando, et al. Potential role of vitamin D receptor gene polymorphism in determining bone phenotype in young male athletes. J. Appl. Physiol. 93:1973–1979, 2002.
    101. Nazarov, I. B., D. R. Woods, H. E. Montgomery, et al. The angiotensin converting enzyme I/D polymorphism in Russian athletes. Eur. J. Hum. Genet. 9:797–801, 2001.
    102. Ortlepp, J. R., J. Metrikat, M. Albrecht, A. von Korff, P. Hanrath, and R. Hoffmann. The vitamin D receptor gene variant and physical activity predicts fasting glucose levels in healthy young men. Diabet. Med. 20:451–454, 2003.
    103. Ortlepp, J. R., J. Metrikat, V.. Mevissen, et al. Relation between the angiotensinogen (AGT) M235T gene polymorphism and blood pressure in a large, homogeneous study population. J. Hum. Hypertens. 17:555–559, 2003.
    104. Ortlepp, J. R., J. Metrikat, K. Vesper, et al. The interleukin-6 promoter polymorphism is associated with elevated leukocyte, lymphocyte, and monocyte counts and reduced physical fitness in young healthy smokers. J. Mol. Med. 81:578–584, 2003.
    105. Otabe, S., K. Clement, C. Dina, et al. A genetic variation in the 5′ flanking region of the UCP3 gene is associated with body mass index in humans in interaction with physical activity. Diabetologia 43:245–249, 2000.
    106. Patel, S., D. R. Woods, N. J. Macleod, et al. Angiotensin-converting enzyme genotype and the ventilatory response to exertional hypoxia. Eur. Respir J. 22:755–760, 2003.
    107. Perusse, L., T. Rankinen, R. Rauramaa, M. A. Rivera, B. Wolfarth, and C. Bouchard. The human gene map for performance and health-related fitness phenotypes: the 2002 update. Med. Sci. Sports Exerc. 35:1248–1264, 2003.
    108. Peters, W. R., J. P. MacMurry, J. Walker, R. J. Giese, Jr., and D. E. Comings. Phenylethanolamine N-methyltransferase G-148A genetic variant and weight loss in obese women. Obes. Res. 11:415–419, 2003.
    109. Pisciotta, L., A. Cantafora, A. Piana, et al. Physical activity modulates effects of some genetic polymorphisms affecting cardiovascular risk in men aged over 40 years. Nutr. Metab. Cardiovasc. Dis. 13:202–210, 2003.
    110. Postma, A. V., I. Denjoy, T. M. Hoorntje, et al. Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia. Circ. Res. 91:e21–e26, 2002.
    111. Prior, S. J., J. M. Hagberg, D. A. Phares, et al. Sequence variation in hypoxia-inducible factor 1alpha (HIF1A): association with maximal oxygen consumption. Physiol. Genomics 15:20–26, 2003.
    112. Priori, S. G., C. Napolitano, N. Tiso, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 103:196–200, 2001.
    113. Pulkes, T., A. Siddiqui, J. A. Morgan-Hughes, and M. G. Hanna. A novel mutation in the mitochondrial tRNA(TYr) gene associated with exercise intolerance. Neurology 55:1210–1212, 2000.
    114. Rankinen, T., P. An, L. Perusse, et al. Genome-wide linkage scan for exercise stroke volume and cardiac output in the HERITAGE Family Study. Physiol. Genomics 10:57–62, 2002.
    115. Rankinen, T., P. An, T. Rice, et al. Genomic scan for exercise blood pressure in the Health, Risk Factors, Exercise Training and Genetics (HERITAGE) Family Study. Hypertension 38:30–37, 2001.
    116. Rankinen, T., J. Gagnon, L. Perusse, et al. AGT M235T and ACE ID polymorphisms and exercise blood pressure in the HERITAGE Family Study. Am. J. Physiol. Heart Circ. Physiol. 279:H368–H374, 2000.
    117. Rankinen, T., L. Perusse, I. Borecki, et al. The Na(+)-K(+)-ATPase alpha2 gene and trainability of cardiorespiratory endurance: the HERITAGE family study. J. Appl. Physiol. 88:346–351, 2000.
    118. Rankinen, T., L. Perusse, J. Gagnon, et al. Angiotensin-converting enzyme ID polymorphism and fitness phenotype in the HERITAGE Family Study. J. Appl. Physiol. 88:1029–1035, 2000.
    119. Rankinen, T., L. Perusse, R. Rauramaa, M. A. Rivera, B. Wolfarth, and C. Bouchard. The human gene map for performance and health-related fitness phenotypes. Med. Sci. Sports Exerc. 33:855–867, 2001.
    120. Rankinen, T., T. Rice, A. Boudreau, et al. Titin is a candidate gene for stroke volume response to endurance training: the HERITAGE Family Study. Physiol. Genomics 15:27–33, 2003.
    121. Rankinen, T., T. Rice, A. S. Leon, et al. G protein beta 3 polymorphism and hemodynamic and body composition phenotypes in the HERITAGE Family Study. Physiol. Genomics 8:151–157, 2002.
    122. Rankinen, T., T. Rice, L. Perusse, et al. NOS3 Glu298Asp genotype and blood pressure response to endurance training: the HERITAGE family study. Hypertension 36:885–889, 2000.
    123. Rauramaa, R., R. Kuhanen, T. A. Lakka, et al. Physical exercise and blood pressure with reference to the angiotensinogen M235T polymorphism. Physiol. Genomics 10:71–77, 2002.
    124. Rauramaa, R., S. Vaisanen, A. Nissinen, et al. Physical activity, fibrinogen plasma level and gene polymorphisms in postmenopausal women. Thromb. Haemost. 78:840–844, 1997.
    125. Rauramaa, R., S. B. Vaisanen, R. Kuhanen, I. Penttila, and C. Bouchard. The RsaI polymorphism in the alpha-fibrinogen gene and response of plasma fibrinogen to physical training: a controlled randomised clinical trial in men. Thromb. Haemost. 83:803–806, 2000.
    126. Remes, T., S. B. Vaisanen, A. Mahonen, et al. Aerobic exercise and bone mineral density in middle-aged finnish men: a controlled randomized trial with reference to androgen receptor, aromatase, and estrogen receptor alpha gene polymorphisms. Bone 32:412–420, 2003.
    127. Rice, T., Y. C. Chagnon, L. Perusse, et al. A genomewide linkage scan for abdominal subcutaneous and visceral fat in black and white families: The HERITAGE Family Study. Diabetes 51:848–855, 2002.
    128. Rice, T., T. Rankinen, Y. C. Chagnon, et al. Genomewide linkage scan of resting blood pressure: HERITAGE Family Study: Health, Risk Factors, Exercise Training, and Genetics. Hypertension 39:1037–1043, 2002.
    129. Rico-Sanz, J., T. Rankinen, D. R. Joanisse, et al. Associations between cardiorespiratory responses to exercise and the C34T AMPD1 gene polymorphism in the HERITAGE Family Study. Physiol. Genomics 14:161–166, 2003.
    130. Rivera, M. A., F. T. Dionne, J. A. Simoneau, et al. Muscle-specific creatine kinase gene polymorphism and VO2max in the HERITAGE Family Study. Med. Sci. Sports Exerc. 29:1311–1317, 1997.
    131. Rivera, M. A., M. Echegaray, T. Rankinen, et al. Angiogenin gene-race interaction for resting and exercise BP phenotypes: the HERITAGE Family Study. J. Appl. Physiol. 90:1232–1238, 2001.
    132. Rivera, M. A., M. Echegaray, T. Rankinen, et al. TGF-beta(1) gene-race interactions for resting and exercise blood pressure in the HERITAGE Family Study. J. Appl. Physiol. 91:1808–1813, 2001.
    133. Rivera, M. A., L. Perusse, J. A. Simoneau, et al. Linkage between a muscle-specific CK gene marker and VO2max in the HERITAGE Family Study. Med. Sci. Sports Exerc. 31:698–701, 1999.
    134. Rodas, G., G. Ercilla, C. Javierre, et al. Could the A2A11 human leucocyte antigen locus correlate with maximal aerobic power?Clin. Sci. (Colch.) 92:331–333, 1997.
      135. Roth, S. M., E. J. Metter, M. R. Lee, B. F. Hurley, and R. E. Ferrell. C174T polymorphism in the CNTF receptor gene is associated with fat-free mass in men and women. J. Appl. Physiol. 95:1425–1430, 2003.
      136. Roth, S. M., M. A. Schrager, R. E. Ferrell, et al. CNTF genotype is associated with muscular strength and quality in humans across the adult age span. J. Appl. Physiol. 90:1205–1210, 2001.
      137. Sakane, N., T. Yoshida, T. Umekawa, A. Kogure, Y. Takakura, and M. Kondo. Effects of Trp64Arg mutation in the beta 3-ad-renergic receptor gene on weight loss, body fat distribution, glycemic control, and insulin resistance in obese type 2 diabetic patients. Diabetes Care 20:1887–1890, 1997.
      138. Sayer, A. A., H. Syddall, S. D. O’Dell, et al. Polymorphism of the IGF2 gene, birth weight and grip strength in adult men. Age Ageing 31:468–470, 2002.
      139. Scanavini, D., F. Bernardi, E. Castoldi, F. Conconi, and G. Mazzoni. Increased frequency of the homozygous II ACE genotype in Italian Olympic endurance athletes. Eur. J. Hum. Genet. 10:576–577, 2002.
      140. Scholte, H. R., R. N. Van Coster, P. C. de Jonge, et al. Myopathy in very-long-chain acyl-CoA dehydrogenase deficiency: clinical and biochemical differences with the fatal cardiac phenotype. Neuromuscul. Disord. 9:313–319, 1999.
      141. Schuelke, M., H. Krude, B. Finckh, et al. Septo-optic dysplasia associated with a new mitochondrial cytochrome b mutation. Ann. Neurol. 51:388–392, 2002.
      142. Schwartz, P. J., S. G. Priori, C. Spazzolini, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 103:89–95, 2001.
      143. Seibert, M. J., Q. L. Xue, L. P. Fried, and J. D. Walston. Polymorphic variation in the human myostatin (GDF-8) gene and association with strength measures in the Women’s Health and Aging Study II cohort. J. Am. Geriatr. Soc. 49:1093–1096, 2001.
      144. Selvadurai, H. C., K. O. McKay, C. J. Blimkie, P. J. Cooper, C. M. Mellis, and P. P. Van Asperen. The relationship between genotype and exercise tolerance in children with cystic fibrosis. Am. J. Respir. Crit. Care Med. 165:762–765, 2002.
      145. Sengler, C., A. Heinzmann, S. P. Jerkic, et al. Clara cell protein 16 (CC16) gene polymorphism influences the degree of airway responsiveness in asthmatic children. J. Allergy Clin. Immunol. 111:515–519, 2003.
      146. Senti, M., C. Aubo, R. Elosua, J. Sala, M. Tomas, and J. Marrugat. Effect of physical activity on lipid levels in a population-based sample of men with and without the Arg192 variant of the human paraoxonase gene. Genet. Epidemiol. 18:276–286, 2000.
      147. Sherman, J. B., N. Raben, C. Nicastri, et al. Common mutations in the phosphofructokinase-M gene in Ashkenazi Jewish patients with glycogenesis VII–and their population frequency. Am. J. Hum. Genet. 55:305–313, 1994.
      148. Shiwaku, K., A. Nogi, E. Anuurad, et al. Difficulty in losing weight by behavioral intervention for women with Trp64Arg polymorphism of the beta3-adrenergic receptor gene. Int. J. Obes. Relat. Metab. Disord. 27:1028–1036, 2003.
      149. Sofowora, G. G., V. Dishy, M. Muszkat, et al. A common beta1-adrenergic receptor polymorphism (Arg389Gly) affects blood pressure response to beta-blockade. Clin. Pharmacol. Ther. 73:366–371, 2003.
      150. Sun, G., J. Gagnon, Y. C. Chagnon, et al. Association and linkage between an insulin-like growth factor-1 gene polymorphism and fat free mass in the HERITAGE Family Study. Int. J. Obes. Relat. Metab. Disord. 23:929–935, 1999.
      151. Taggart, R. T., D. Smail, C. Apolito, and G. D. Vladutiu. Novel mutations associated with carnitine palmitoyltransferase II deficiency. Hum. Mutat. 13:210–220, 1999.
      152. Taimela, S., T. Lehtimaki, K. V. Porkka, L. Rasanen, and J. S. Viikari. The effect of physical activity on serum total and low-density lipoprotein cholesterol concentrations varies with apolipoprotein E phenotype in male children and young adults: the Cardiovascular Risk in Young Finns Study. Metabolism 45:797–803, 1996.
      153. Tajima, O., N. Ashizawa, T. Ishii, et al. Interaction of the effects between vitamin D receptor polymorphism and exercise training on bone metabolism. J. Appl. Physiol. 88:1271–1276, 2000.
      154. Taroni, F., E. Verderio, F. Dworzak, P. J. Willems, P. Cavadini, and S. DiDonato. Identification of a common mutation in the carnitine palmitoyltransferase II gene in familial recurrent myo-globinuria patients. Nat. Genet. 4:314–320, 1993.
      155. Tiret, L., O. Poirier, V. Hallet, et al. The Lys198Asn polymorphism in the endothelin-1 gene is associated with blood pressure in overweight people. Hypertension 33:1169–1174, 1999.
      156. Tomas, M., R. Elosua, M. Senti, et al. Paraoxonase1–192 polymorphism modulates the effects of regular and acute exercise on paraoxonase1 activity. J. Lipid Res. 43:713–720, 2002.
      157. Toscano, A., S. Tsujino, G. Vita, S. Shanske, C. Messina, and S. Dimauro. Molecular basis of muscle phosphoglycerate mutase (PGAM-M) deficiency in the Italian kindred. Muscle Nerve 19:1134–1137, 1996.
      158. Tsujino, S., S. Servidei, P. Tonin, S. Shanske, G. Azan, and S. DiMauro. Identification of three novel mutations in non-Ashkenazi Italian patients with muscle phosphofructokinase deficiency. Am. J. Hum. Genet. 54:812–819, 1994.
      159. Tsujino, S., S. Shanske, A. K. Brownell, R. G. Haller, and S. DiMauro. Molecular genetic studies of muscle lactate dehydrogenase deficiency in white patients. Ann. Neurol. 36:661–665, 1994.
      160. Tsujino, S., S. Shanske, and S. DiMauro. Molecular genetic heterogeneity of myophosphorylase deficiency (McArdle’s disease). N. Engl. J. Med. 329:241–245, 1993.
      161. Tsujino, S., S. Shanske, and S. DiMauro. Molecular genetic heterogeneity of phosphoglycerate kinase (PGK) deficiency. Muscle Nerve 3:S45–S49, 1995.
      162. Tsujino, S., S. Shanske, S. Sakoda, G. Fenichel, and S. DiMauro. The molecular genetic basis of muscle phosphoglycerate mutase (PGAM) deficiency. Am. J. Hum. Genet. 52:472–477, 1993.
      163. Tsuritani, I., K. S. Brooke-Wavell, S. S. Mastana, P. R. Jones, A. E. Hardman, and Y. Yamada. Does vitamin D receptor polymorphism influence the response of bone to brisk walking in postmenopausal women?Horm. Res. 50:315–319, 1998.
        164. Tuomilehto, J., J. Lindstrom, J. G. Eriksson, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N. Engl. J. Med. 344:1343–1350, 2001.
        165. Vaisanen, S. B., S. E. Humphries, L. A. Luong, I. Penttila, C. Bouchard, and R. Rauramaa. Regular exercise, plasminogen activator inhibitor-1 (PAI-1) activity and the 4G/5G promoter polymorphism in the PAI-1 gene. Thromb. Haemost. 82:1117–1120, 1999.
        166. Van Pottelbergh, I., S. Goemaere, and J. M. Kaufman. Bio-available estradiol and an aromatase gene polymorphism are determinants of bone mineral density changes in men over 70 years of age. J. Clin. Endocrinol. Metab. 88:3075–3081, 2003.
        167. Van Pottelbergh, I., S. Goemaere, L. Nuytinck, A. De Paepe, and J. M. Kaufman. Association of the type I collagen alpha1 Sp1 polymorphism, bone density and upper limb muscle strength in community-dwelling elderly men. Osteoporos. Int. 12:895–901, 2001.
        168. Vissing, J., M. B. Salamon, P. Arlien-Soborg, et al. A new mitochondrial tRNA(Met) gene mutation in a patient with dystrophic muscle and exercise intolerance. Neurology 50:1875–1878, 1998.
        169. Vives-Bauza, C., J. Gamez, M. Roig, et al. Exercise intolerance resulting from a muscle-restricted mutation in the mitochondrial tRNA(Leu (CUN)) gene. Ann. Med. 33:493–496, 2001.
        170. Vladutiu, G. D., M. J. Bennett, N. M. Fisher, et al. Phenotypic variability among first-degree relatives with carnitine palmitoyl-transferase II deficiency. Muscle Nerve 26:492–498, 2002.
        171. Vladutiu, G. D., M. J. Bennett, D. Smail, L. J. Wong, R. T. Taggart, and H. B. Lindsley. A variable myopathy associated with heterozygosity for the R503C mutation in the carnitine palmitoyltransferase II gene. Mol. Genet. Metab. 70:134–141, 2000.
        172. Vorgerd, M., J. Karitzky, M. Ristow, et al. P. Muscle phosphofructokinase deficiency in two generations. J. Neurol. Sci. 141:95–99, 1996.
        173. Wagoner, L. E., L. L. Craft, B. Singh, et al. Polymorphisms of the beta(2)-adrenergic receptor determine exercise capacity in patients with heart failure. Circ. Res. 86:834–840, 2000.
        174. Wagoner, L. E., L. L. Craft, P. Zengel, et al. Polymorphisms of the beta1-adrenergic receptor predict exercise capacity in heart failure. Am. Heart J. 144:840–846, 2002.
        175. Wang, Q., M. E. Curran, I. Splawski, et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat. Genet. 12:17–23, 1996.
        176. Williams, A. G., M. P. Rayson, M. Jubb, et al. The ACE gene and muscle performance. Nature 403:614, 2000.
        177. Wolfarth, B., M. A. Rivera, J. M. Oppert, et al. A polymorphism in the alpha2a-adrenoceptor gene and endurance athlete status. Med. Sci. Sports Exerc. 32:1709–1712, 2000.
        178. Woods, D., M. Hickman, Y. Jamshidi, et al. Elite swimmers and the D allele of the ACE I/D polymorphism. Hum. Genet. 108:230–232, 2001.
        179. Woods, D., G. Onambele, R. Woledge, et al. Angiotensin-I converting enzyme genotype-dependent benefit from hormone replacement therapy in isometric muscle strength and bone mineral density. J. Clin. Endocrinol. Metab. 86:2200–2204, 2001.
        180. Woods, D. R., M. World, M. P. Rayson, et al. Endurance enhancement related to the human angiotensin I-converting enzyme I-D polymorphism is not due to differences in the cardio-respiratory response to training. Eur. J. Appl. Physiol. 86:240–244, 2002.
        181. Yang, N., D. G. MacArthur, J. P. Gulbin, et al. ACTN3 genotype is associated with human elite athletic performance. Am. J. Hum. Genet. 73:627–631, 2003.
        182. Zhang, B., T. Sakai, S. Miura, et al. Association of angiotensin-converting-enzyme gene polymorphism with the depressor response to mild exercise therapy in patients with mild to moderate essential hypertension. Clin. Genet. 62:328–333, 2002.
        183. Zhao, B., S. M. Moochhala, S. Tham, et al. Relationship between angiotensin-converting enzyme ID polymorphism and VO(2max) of Chinese males. Life Sci. 73:2625–2630, 2003.
        Keywords:

        CANDIDATE GENES; QUANTITATIVE TRAIT LOCI; LINKAGE; GENETIC VARIANTS; MITOCHONDRIAL GENOME; NUCLEAR GENOME

        ©2004The American College of Sports Medicine