SPECIAL REPORT

The Human Gene Map for Performance and Health-Related Fitness Phenotypes: The 2004 Update

BERND WOLFARTH1, MOLLY S. BRAY2, JAMES M. HAGBERG3, LOUIS PE´ RUSSE4, RAINER RAURAMAA5, MIGUEL A. RIVERA6, STEPHEN M. ROTH3, TUOMO RANKINEN7, and CLAUDE BOUCHARD7 1Department of Preventive and Rehabilitative Sports Medicine, Technical University Munich, Munich, GERMANY; 2Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX; 3Department of Kinesiology, College of Health and Human Performance, University of Maryland, College Park, MD; 4Division of Kinesiology, Department of Preventive Medicine Laval University, Ste-Foy, Que´bec, CANADA; 5Kuopio Research Institute of Exercise Medicine, Department of Physiology, University of Kuopio and Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, FINLAND; 6Department of Physiology and Department of Physical Medicine, University of Puerto Rico School of Medicine, San Juan, PR; and 7Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA

ABSTRACT WOLFARTH, B., M. S. BRAY, J. M. HAGBERG, L. PE´ RUSSE, R. RAURAMAA, M. A. RIVERA, S. M. ROTH, T. RANKINEN, and C. BOUCHARD. The Human Gene Map for Performance and Health-Related Fitness Phenotypes: The 2004 Update. Med. Sci. Sports Exerc., Vol. 37, No. 6, pp. 881–903, 2005. We began this series in 2000 with the aim of making available in an easily accessible format all the advances on the genetic basis of a large family of exercise-related traits. The current review presents the 2004 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 2004. 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 . Negative studies are reviewed but a gene or locus must be supported by at least one positive study before being inserted on the map. One new feature is that we have incorporated the genes whose sequence variants have been associated with either the level of physical activity or indicators of sedentarism. By the end of 2000, in the early version of the gene map, 29 loci were depicted. In contrast, the 2004 human gene map for physical performance and health-related phenotypes includes 140 autosomal gene entries and quantitative trait loci, plus four on the X chromosome. Moreover, there are 16 mitochondrial genes in which sequence variants have been shown to influence relevant fitness and performance phenotypes. Thus, the map is growing in complexity and progress is being made. The number of laboratories and scientists concerned by the role of genes and sequence variations in exercise-related traits is rising. But exercise science and sports medicine is generally lagging behind in terms of utilizing the advances in genetic and genomic technologies. Key Words: CANDIDATE GENES, QUANTITATIVE TRAIT LOCI, LINKAGE, GENETIC VARIANTS, MITOCHONDRIAL GENOME, NUCLEAR GENOME, GENETICS

his paper constitutes the fifth installment in the series on marily based on the journals available in MEDLINE, the Na- the human gene map for performance and health-re- tional Library of Medicine’s publication database covering the Tlated fitness phenotypes published in this journal. It fields of life sciences, biomedicine and health, using a combi- covers the peer-reviewed literature published by the end of nation of key words (e.g., exercise, physical activity, perfor- December 2004. The search for relevant publications is pri- mance, training, genetics, genotype, polymorphism, mutation, and linkage). Other sources include personal reprint collections of the authors and documents made available to us by col- Address for correspondence: Claude Bouchard, Ph.D., Human Genomics leagues who are publishing in this field. The electronic pre- Laboratory Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808-4124; E-mail: [email protected]. publications, that is, articles that are made available on the web Submitted for publication March 2005. site of a journal before being published in print are not included Accepted for publication April 2005. in the current review. The goal of the human gene map for 0195-9131/05/3706-0881/0 fitness and performance is to review all genetic loci and mark-

MEDICINE & SCIENCE IN SPORTS & EXERCISE® ers shown to be related to physical performance or health- Copyright © 2005 by the American College of Sports Medicine related fitness phenotypes in at least one study. Negative stud- DOI: 10.1249/01.mss.0000168663.55604.1d ies are briefly reviewed for a balanced presentation of the 881 FIGURE 1— The 2004 human performance and health-related fitness gene map. The map includes all gene entries and QTL that have shown associations or linkages with exercise-related phenotypes summarized in the article. The and their regions are from the Gene Map of the web site hosted by the National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD (URL:http//www.ncbi.nlm.nih.gov/). The chromosome number and the size of each chromosome in megabases (Mb) are given at the top and bottom of the chromosomes, respectively. Loci abbreviations and full names are given in Table 1. evidence. However, the nonsignificant results are not incorpo- search under the general theme of the status of the human rated in the summary tables. obesity gene map (125), or can consult the following e-ver- The physical performance phenotypes for which genetic sion of this other map: http://obesitygene.pbrc.edu. data are available include cardiorespiratory endurance, elite The studies incorporated in the review are fully refer- endurance athlete status, muscle strength, other muscle per- enced so that the interested reader can access the original formance traits, and exercise intolerance of variable de- papers. Of interest to some could be the early observations grees. Consistent with the previous reviews, the phenotypes made on athletes, particularly Olympic athletes. The results of health-related fitness retained are grouped under the of these case-control studies based on common red blood following categories: hemodynamic traits including exercise cell were essentially negative and are not reviewed heart rate, blood pressure, and heart morphology; anthro- in this edition of the map. The interested reader can consult pometry and body composition; insulin and glucose metab- the first installment of the gene map for a complete sum- olism; and blood , , and hemostatic factors. mary of these early reports (138). Here, we are not concerned by the effects of specific genes Figure 1 depicts the 2004 synthesis of the human perfor- on these phenotypes unless the focus is on exercise, exercise mance and health-related fitness gene map for the auto- training, athletes, or active people compared with controls or inactive individuals, or exercise intolerance. This is par- somes and the X chromosome. The 2004 version includes ticularly important for the genetic studies that have focused 34 additional gene entries and quantitative trait loci (QTL) on body mass index, adiposity, fat-free mass, adipose tissue and markers as compared with the 2003 version (139). We distribution, and various abdominal fat phenotypes. If there have also depicted in Figure 2 the gene loci in the mito- were no exercise-related issues in those studies, the papers chondrial DNA in which sequence variants have been are not considered here. However, the interested reader can shown to be associated with fitness and performance phe- obtain a full expose of these other studies in one of our notypes. Table 1 provides a list of all genes or loci, cyto- complementary papers published every year in Obesity Re- genic locations, and conventional symbols used in this re-

882 Official Journal of the American College of Sports Medicine http://www.acsm-msse.org with more athletes carrying the I-allele (196). Participants of two consecutive South African Ironman Triathlons were investigated with regard to the ACE I/D polymorphism. The fastest 100 South African-born finishers had a higher fre- quency of the I allele, compared with 166 South African- born controls. In addition the authors found a significant linear trend for the allele distribution among the fastest 100 finishers, the slowest 100 finishers and 199 South African- born controls. The frequencies of the I allele were 0.52, 0.48, and 0.42, respectively (20). In the same group of triathletes, allele and genotype frequencies of the Ϫ55 C/T polymorphism of the uncoupling protein 3 (UCP3) gene did not differ between the fast and slow finishers (60). Cross-sectional association studies. Five new studies published in 2004 investigated cross-sectional asso- ciations between DNA sequence variation and endurance– related phenotypes (Table 3). McCole et al. (99) investi- gated postmenopausal women and found an association between the adrenergic receptor ␤2(ADRB2) Gln27Glu

genotype and arterial-venous oxygen difference (a-vDO2) during submaximal and maximal exercise. The Gln/Gln FIGURE 2— Mitochondrial genes that have been shown to be associ- Ϫ1 ated with exercise intolerance, fitness, or performance-related pheno- homozygote women showed 1.2–2 mL·100 mL greater types. The location of the specific sequence variants is defined in Tables a-vDO2 compared with the Glu/Glu carriers. In the same 3 and 14. The mitochondrial DNA locations are from: http://www.mi- cohort, the Gln carriers had higher values for maximum tomap.org. ˙ oxygen uptake (VO2max) than the Glu carriers. In addition, the Trp64Arg polymorphism of the adrenergic receptor ␤3 view. The terminology and symbols used are as defined in (ADRB3) gene was investigated and revealed a significant the footnote to the Tables. difference between the Trp/Trp homozygotes and Trp/Arg The reader will have noticed that the human gene map for heterozygotes with higher V˙ O in the latter group. How- performance and health-related fitness traits is now pro- 2max ever, the association disappeared after adjusting for habitual duced by an expanded team of scientists. Indeed, the orig- physical activity level. All other phenotypes showed no inal team put together by T. Rankinen and C. Bouchard, significant associations with the ADRB3 polymorphism which included L. Pe´russe, R. Rauramaa, M. A. Rivera, and (99). B. Wolfarth, has now been reinforced by contributions from Delta efficiency (DE) was significantly associated with M. S. Bray, J. M. Hagberg, and S. M. Roth. This reflects the the Bradykinin receptor B2 (BDKRB2) genotype (ϩ9/9) in fact that the project is growing in scope and complexity. We a study including 115 sedentary men and women. The believe that this expanded team will be able to provide a BDKRB2 genotype (Ϫ9/9) had the highest DE and in a thorough coverage of all the advances in the field and make multivariate analysis, including gender as a covariate, the it possible to deliver a publication ready product in a timely BDKRB2 genotype accounted for 11.2% of the variance in fashion. It remains our collective goal to make this publi- DE. In an interaction analysis including also the ACE I/D cation a useful resource for those who have to teach the role genotype, those with the highest predicted kinin receptor of inheritance on fitness and performance traits and the activity (ACE I/I and BDKRB2 Ϫ9/9) had a significantly impact of genetic variation on the health of human beings. higher DE compared with those with the lowest kinin re- It is also our hope that the yearly update of the fitness and ceptor activity. The ACE D/D and BDKRB2 ϩ9/ϩ9 com- performance gene map will be found useful to the exercise bination was also found more often in a group of long- scientists and the sports medicine community. distance runners competing in short endurance events than in athletes from long-distance events (Ͼ5000 m) (210).

PERFORMANCE PHENOTYPES Oxygen delivery (DO2) in chronic obstructive pulmonary disease (COPD) patients was found to be associated with the Endurance Phenotypes ACE I/D genotype after a graded exercise test on an er-

Case-control studies. The case-control studies re- gometer. In patients with the D/D genotype, DO2 after porting statistically significant differences in allele and ge- exercise was significantly lower compared with patients notype frequencies between endurance athletes and seden- carrying the I/D and the I/I genotype. However, no differ- tary controls are summarized in Table 2. Three papers were ence was found between genotype groups with regard to published in 2004. In a Turkish study comparing 80 uni- DO2 in the resting state (74). The ACE I/D polymorphism versity athletes with the same number of healthy volunteers, was targeted as a candidate gene for exercise heat tolerance Turgut and coworkers found a significant difference for the in a study by Heled and coworkers (57). After exposing 58 angiotensin I converting (ACE) I/D polymorphism, subjects to a 2-h exercise heat-tolerance test, they found the

HUMAN FITNESS GENE MAP 2004 Medicine & Science in Sports & Exerciseா 883 TABLE 1. Symbols, full names, and cytogenic location of nuclear and mitochondrial TABLE 1. Continued. genes of the 2004 human gene map for performance and health-related fitness Gene or phenotypes. Locus Name Location Gene or MTND5 NADH dehydrogenase subunit 5 mtDNA 12337 Locus Name Location – 14148 AB MTTE Transfer RNA, mitochondrial, glutamic acid mtDNA 14674 – 14742 MTTI Transfer RNA, mitochondrial, isoleucine mtDNA 4263- ACADVL Acyl-Coenzyme A dehydrogenase, very long 17p13-p11 4331 chain MTTK Transfer RNA, mitochondrial, lysine mtDNA 8295 ACE Angiotensin I converting enzyme 17q23 – 8364 ACTN3 Actinin, alpha 3 11q13-q14 MTTL1 Transfer RNA, mitochondrial, leucine 1 mtDNA 3230 ADRA2A Adrenergic, alpha-2A-, receptor 10q24-q26 (UUR) – 3304 ADRB1 Adrenergic, beta-1-, receptor 10q24-q26 MTTL2 Transfer RNA, mitochondrial, leucine 2 mtDNA 12266 ADRB2 Adrenergic, beta-2, receptor 5q31-q32 (CUN) – 12336 ADRB3 Adrenergic, beta-3, receptor 8p12-p11.2 MTTM Transfer RNA, mitochondrial, methionine mtDNA 4402 AGT Angiotensinogen 1q42-q43 – 4469 AMPD1 Adenosine monophosphate deaminase 1 1p13 MTTS1 Transfer RNA, mitochondrial, serine 1 mtDNA 7445 ANG , , RNase A family, 14q11.1-q11.2 (UCN) – 7516 5 MTTT Transfer RNA, mitochondrial, threonine mtDNA 15888 APOA2 A-II 1q21-q23 – 15953 APOC3 -III 11q23.1-q23.2 MTTY Transfer RNA, mitochondrial, tyrosine mtDNA 5826 APOE 19q13.2 – 5891 ATP1A2 ATPase, Naϩ/Kϩ transporting, alpha 2 (ϩ) 1q21-q23 polypeptide ATP1B1 ATPase, Naϩ/Kϩ transporting, beta 1 1q22-q25 NOPQRSTUV polypeptide BDKRB2 Bradykinin receptor B2 14q32.1-q32.2 NOS3 Nitric oxide synthase 3 (endothelial cell) 7q36 BRCA1 Breast cancer 1, early onset 17q21 NPY Neuropeptide Y 7p15.1 BRCA2 Breast cancer 2, early onset 13q12.3 NR3C1 Nuclear receptor subfamily 3, group C, 5q31 member 1 (glucocorticoid receptor) PFKM Phosphofructokinase, muscle 12q13.3 CDEFG PGAM2 Phosphoglycerate mutase 2 (muscle) 7p13-p12 PGK1 Phosphoglycerate kinase 1 Xq13 CASQ2 Calsequestrin 2 (cardiac muscle) 1p13.3-p11 PHKA1 Phosphorylase kinase, alpha 1 (muscle) Xq12-q13 CASR Calcium-sensing receptor 3q21-q24 PLCG1 C, gamma 1 20q12-q13.1 CETP Cholesteryl ester transfer protein, plasma 16q21 PNMT Phenylethanolamine N-methyltransferase 17q21-q22 CFTR Cystic fibrosis transmembrane conductance 7q31.2 PON1 1 7q21.3 regulator, ATP-binding cassette (sub- PON2 Paraoxonase 2 7q21.3 family C, member 7) PPARA Peroxisome proliferative activated receptor, 22q13.31 CKM Creatine kinase, muscle 19q13.2-q13.3 alpha CNTF Ciliary neurotrophic factor 11q12.2 PPARG Peroxisome proliferative activated receptor, 3p25 CNTFR Ciliary neurotrophic factor receptor 9p13 gamma CPT2 Carnitine palmitoyltransferase II 1p32 PPARGC1A Peroxisome proliferative activated receptor, 4p15.1 COL1A1 Collagen, type I, alpha 1 17q21.3-q22.1 gamma, coactivator 1, alpha COMT Catechol-O-methyltransferase 22q11.21 PYGM Phosphorylase, glycogen, muscle 11q12-q13.2 CYP19A1 Cytochrome P450, family 19, subfamily A, 15q21.1 RYR2 Ryanodine receptor 2 (cardiac) 1q42.1-q43 polypeptide 1 (aromatase) S100A1 S100 calcium binding protein A1 1q21 DRD2 Dopamine receptor D2 11q23 SCGB1A1 Secretoglobin, family 1A, member 1 11q12.3-q13.1 EDN1 Endothelin 1 6p24.1 SERPINE1 serine (or cysteine) proteinase inhibitor, 7q21.3-q22 ENO3 Enolase 3 (beta, muscle) 17pter-p11 clade E (nexin, plasminogen activator ESR1 Estrogen receptor 1 6q25.1 inhibitor type 1), member 1 FABP2 Fatty acid binding protein 2, intestinal 4q28-q31 SGCA Sarcoglycan, alpha (50kDa dystrophin- 17q21 FGA Fibrinogen, A alpha polypeptide 4q28 associated glycoprotein) FGB Fibrinogen, B beta polypeptide 4q28 SGCG Sarcoglycan, gamma (35kDA dystrophin- GDF8 (MSTN) Growth differentiation factor 8 (myostatin) 2q32.2 associated glycoprotein) GK Glycerol kinase Xp21.3 STS Steroid (microsomal) Xp22.32 GNB3 Guanine nucleotide binding protein (G 12p13 SUR Sulfonylurea receptor 11p15.1 protein), beta polypeptide 3 TGFB1 Transforming growth factor, beta 1 19q13.1 GPR10 G-protein coupled receptor 10 10q26.13 TNF Tumor necrosis factor (TNF superfamily, 6p21.3 member 2) TTN Titin 2q31 HIKLM UCP1 Uncoupling protein 1 4q28-q31 UCP2 Uncoupling protein 2 11q13 HIF1A Hypoxia-inducible factor 1, alpha subunit 14q21-q24 UCP3 Uncoupling protein 3 11q13 HLA-A Major histocompatibility complex, class I, A 6p21.3 VDR Vitamin D (1,25 –dihydroxyvitamin D3) 12q12-q14 HP Haptoglobin 16q22.1 receptor IGF1 Insulin-like growth factor 1 12q22-q23 The gene symbols, names and cytogenetic locations are from the Locus Link Web IGF2 Insulin-like growth factor 2 11p15.5 IGFBP1 Insulin-like growth factor binding protein 1 7p13-p12 site (http://www.ncbi.nlm.nih.gov/LocusLink) available from the National Center for IL15RA Interleukin 15 receptor, alpha 10p15-p14 Biotechnology Information (NCBI). For mitochondrial DNA, locations are from the IL6 Interleukin 6 7p21 human mitochondrial genome database (http://www.mitomap.org). KCNQ1 Potassium voltage-gated channel, KQT-like 11p15.5 subfamily, member 1 LDHA Lactate dehydrogenase A 11p15.4 LEP Leptin 7q31.3 LEPR Leptin receptor 1p31 relative changes in body core temperature, heat storage, and LIPC , hepatic 15q21-q23 heart rate during the test to be lower in the I-allele carriers LIPG Lipase, endothelial 18q21.1 LPL 8p22 as compared with the D/D genotype group. However, they MTCO1 Cytochrome c oxidase subunit I mtDNA 5904 found no association for various aerobic performance mea- – 7445 ˙ ˙ MTCO2 Cytochrome c oxidase subunit II mtDNA 7586- sures including VO2max and VO2 at anaerobic threshold 8269 MTCO3 Cytochrome c oxidase subunit III mtDNA 9207 (57). In a study including 199 consecutive patients with – 9990 chronic heart failure, peak V˙ O before and after beta-block- MTCYB Cytochrome b mtDNA 14747 2 – 15887 ade did not differ between the ACE I/D genotypes (25). MTND1 NADH dehydrogenase subunit 1 mtDNA 3307 – 4262 Association studies with training response phe- MTND4 NADH dehydrogenase subunit 4 mtDNA 10760 notypes. A cohort of 95 COPD patients was submitted to – 12137 an 8-wk pulmonary rehabilitation program including five

884 Official Journal of the American College of Sports Medicine http://www.acsm-msse.org TABLE 2. Endurance phenotypes and case-control studies (DNA polymorphisms). Athletes Controls

Gene Location N Sports Freq N Freq P Reference ADRA2A 10q24-q26 140 Endurance 6.7/6.7: 0.77 141 6.7/6.7: 0.62 0.037 (214) 6.7/6.3: 0.21 6.7/6.3: 0.34 6.3/6.3: 0.02 6.3/6.3: 0.04 6.7: 0.88 6.7: 0.8 0.011 6.3: 0.12 6.3: 0.2 RR: 0.5 RR: 0.30 RX: 0.45 RX: 0.52 ACTN3 11q13-q14 107 Sprinters XX: 0.06 436 XX: 0.18 Ͻ0.001 (220) R: 0.72 R: 0.56 X: 0.28 X: 0.44 ACE 17q23 64 Endurance II: 0.30 118 II: 0.18 0.03 (42) ID: 0.55 ID: 0.51 0.02 DD: 0.16 DD: 0.32 I: 0.57 I: 0.43 D: 0.43 D: 0.57 79 Running I: 0.57 ref. pop. I: 0.49 0.039 (114) D: 0.43 D: 0.51 25 Mountain-eering n.a. ref. pop. n.a. 0.02 (108) 0.003 60 Elite athletes (cycling, running, handball) II: 0.25 ref. pop. II: 0.16 0.0009 (2) ID: 0.58 ID: 0.45 DD: 0.17 DD: 0.39 I: 0.54 I: 0.38 D: 0.46 D: 0.62 56 Elite swimmers (subsample of 103 II: 0.15 1248 II: 0.24 0.004 (216) swimmers) ID: 0.39 ID: 0.49 DD: 0.46 DD: 0.27 I: 0.34 I: 0.48 D: 0.66 D: 0.52 3035 Short distance athletes Middle-distance II: 0.07 449 II: 0.23 0.001 (117) athletes (subsample of 217 Russian ID: 0.43 ID: 0.52 0.032 athletes) DD: 0.50 DD: 0.24 I: 0.28 I: 0.5 D: 0.72 D: 0.5 II: 0.37 ID: 0.51 DD: 0.12 I: 0.63 D: 0.37 33 Olympic aerobic athletes II: 0.30 152 II: 0.13 0.05 (164) ID: 0.30 ID: 0.43 DD: 0.39 DD: 0.44 I: 0.45 I: 0.34 D: 0.55 D: 0.66 80 University athletes II: 0.14 80 II: 0.11 0.026 (196) ID: 0.36 ID: 0.19 DD: 0.5 DD: 0.70 I: 0.32 I: 0.21 D: 0.68 D: 0.79 100 Triathlon I: 0.52 166 I: 0.42 0.036 (20) D: 0.48 D: 0.58 exercise training sessions per week. Exercise capacity mea- line waist-to-hip ratio (185). Leon and coworkers investi- sured by means of the maximal work load achieved during gated more than 700 subjects from over 200 two-generation exhaustive incremental cycle ergometry (Wmax) was similar families from the HERITAGE Family Study cohort with for all ACE genotypes at baseline. Further analysis revealed regard to the APOE genotype and VO2max status, both that the D/D homozygotes had a smaller Wmax increase than before and after a 20-wk endurance training program. No the I allele carriers (6 vs 14.4 W) (45). An association associations were found between the APOE polymorphism ˙ ˙ between VO2max response and apolipoprotein E (APOE) and VO2max levels, neither in the sedentary state nor in genotype was found after 6 months of supervised exercise response to exercise training (89). training with a maximum of 4 sessions a week at 60–85% of their V˙ O for a total of 50 min per session (185). In 2max Linkage Studies 120 subjects who completed the exercise-training program, the APOE 3/3 homozygotes had a significantly lower in- The HERITAGE Family Study cohort was used for a ˙ ˙ crease in VO2max compared with the two other APOE ge- genomewide linkage scan for VO2max and maximal power ˙ notype groups. This smaller increase in VO2max persisted output (Wmax). In the sedentary state, promising linkages ˙ after adjustment for baseline VO2max, and other parameters, were found in whites for Wmax on chromosome 10q23 ˙ including age, baseline body mass index (BMI), and base- and for VO2max on chromosome 11p15 (Table 4). The

HUMAN FITNESS GENE MAP 2004 Medicine & Science in Sports & Exerciseா 885 TABLE 3. Endurance phenotypes and association studies with candidate genes. Gene Location N Subjects Phenotype P Reference Acute exercise

AMPD1 1p13 400 whites RPE 0.0002 (149) ˙ PPARGC1A 4p15.1 599 healthy subjects PAEE/VO2max, pred 0.009 (35) ˙ ADRB2 5q31-q32 232 HF patients VO2peak 0.0001 (207) ˙ Ͻ 63 PM women VO2max 0.05 (109) ˙ Ͻ 62 PM women VO2max 0.05 62 PM women Max a-vDo2 0.006 (99) Submax a-vDo2 0.004 ˙ HLA-A 6p21.3 8 MZ and 8 DZ twin pairs VO2max 0.001 (157) IL6 7p21 479 young smokers PWCmax 0.002 (120) ˙ Ͻ CFTR 7q31.2 97 CF patients VO2peak 0.05 (170) ˙ Ͻ ADRB1 10q24-q26 263 cardiomyopathy patients VO2peak 0.05 (208) Exercise time Ͻ0.05 ˙ ˙ Ͻ VE/VCO2 0.05 SCGB1A1 11q12.3-q13.1 96 asthmatic children FEV1 after exercise Ͻ0.04 (171) UCP2 11q13 16 healthy subjects Exercise efficiency (gross) 0.02 (16) Exercise efficiency (incremental) 0.03 ˙ HIF1A 14q21-q24 125 whites VO2max (age interaction) NS (55 yr) (130) ˙ 29 blacks VO2max 0.012 (60 yr) 0.005 (65 yr) 0.033 BDKRB2 14q32.1-q32.2 73 male army recruits Muscle efficiency 0.003 (210) 42 female sedentary Caucasians HP 16q22.1 96 PAOD patients Walking distance Ͻ0.05 (26) ˙ Ͻ ACE 17q23 58 PM women VO2max 0.05 (52) Ͻ 47 PM women Max a-vDo2 0.05 91 (79 Caucasians) Running distance 0.009 (114) ˙ 57 cardiomyopathy patients VO2peak 0.05 (1) Exercise time 0.04 ˙ Ͻ 62 PM women VO2max 0.05 (53) 36 COPD patients Postexercise lactate Ͻ0.0001 (70, 71) 43 COPD patients Postexercise lactate 0.01 60 V˙ E during hypoxia 0.008 (124) ˙ 67 Chinese men VO2max 0.04 (222) Ͻ 33 COPD patients DO2 0.05 (74) ˙ CKM 19q13.2-q13.3 160 white parents VO2max 0.007 (153) ˙ 80 white offspring VO2max NS ˙ Ͻ MTND5 12337–14148* 46 VO2max 0.05 (30) ˙ Ͻ MTTT 15888-15953* 46 VO2max 0.05 (30)

Training responses

˙ AMPD1 1p13 400 whites VO2max 0.006 (149) ˙ VEmax 0.006 ˙ ATP1A2 1q21-q23 294 white offspring VO2max 0.018 (136) ˙ VO2max 0.017 ˙ HIF1A 14q21-q24 101 whites VO2max (age interaction) NS (55 yr) (130) 0.005 (60 yr) 0.006 (65 yr) ˙ ACE 17q23 294 white offspring VO2max 0.008–0.150 (137) Power output 0.0001–0.003 78 Army recruits Max. duration for repetitive 0.001 (108) elbow flexion with 15 kg 58 Army recruits Muscle efficiency Ͻ0.025 (211) 58 Army recruits (24II, 26DD) Exercise efficiency 0.02 (219) 95 COPD patients Max work load 0.04 (45) ˙ Ͻ APOE 19q13.2 51 VO2max 0.05 (51) ˙ Ͻ 120 VO2max 0.001 (185) ˙ CKM 19q13.2-q13.3 160 white parents VO2max 0.004 (153) ˙ Ͻ 80 white offspring VO2max 0.025 ˙ Ͻ MTND5 12337–14148* 46 VO2max 0.05 (30) ˙ ˙ ˙ * Mitochondrial DNA; VO2max, maximal oxygen uptake; VE/VCO2, ratio of ventilation to carbon dioxide consumption; Wmax, maximal power output; a-vDO2, arterial-venous oxygen difference; PM, postmenopausal; HF, heart failure; MZ, monozygous; DZ, dizygous; CAD, coronary artery disease; CF, cystic fibrosis; exercise efficiency, decrease in oxygen consumption on given workloads; PAOD, peripheral arterial occlusive disease; V˙ E, ventilation; RPE, rating of perceived exertion; PWC, physical working capacity; FEV, forced

expiratory volume; DO2, oxygen delivery.

˙ strongest evidence of linkage for the training response tive evidence of linkage for VO2max training response ˙ was found in the chromosomal regions 1p31 (VO2max in were located on 4q27, 7q34, and 13q12 in whites and on blacks) and 5q23 (Wmax in whites). Suggestive evidence 16q22 and 20q13.1 in blacks. Training induced changes of linkage was found on 1p31, 7q32, and 7q36 for base- in Wmax showed suggestive linkages on 1q21 and 4p13 as ˙ line VO2max in blacks and on 13q33 and 18q12 for well as on 1q22 and 13q11 in blacks and whites, respec- baseline Wmax in whites. The markers showing sugges- tively (150).

886 Official Journal of the American College of Sports Medicine http://www.acsm-msse.org TABLE 4. Linkage studies with endurance and strength phenotypes. Gene Marker Location N Pairs Phenotype P Reference ˙ ˙ LEPR 1p31 90 blacks VO2max VO2max 0.0017 (150) 102 blacks 0.01 ˙ ATP1A2 1q21-q23 309 white VO2max Wmax 0.054 (136) 0.003

QTL S100STU1 1q21 316 white Wmax 0.0091 (150) QTL D1S398 1q22 90 blacks Wmax 0.0033 (150) QTL D2S118 2q32.2 204 white Knee extension 0.0002 (61) Knee flexion 0.004

QTL D4S1627 4p13 315 white Wmax 0.0062 (150) ˙ QTL FABP2 4q28-q31 315 white VO2max 0.009 (10, 150) OTL D5S1505 5q23 315 white Wmax 0.002 (150) QTL D6S1051 6p21.3 204 white Knee extension 0.009 (61) Knee flexion 0.004 ˙ QTL LEP 7q32 102 blacks VO2max 0.0068 (150) ˙ QTL D7S495 7q34 315 white VO2max 0.0089 (150) ˙ QTL NOS3 7q36 102 blacks VO2max 0.003 (150) OTL D10S677 10q23 315 white Wmax 0.0014 (150) QTL D11S4138 11p15 204 white Knee extension 0.004 (61) Knee flexion 0.002 ˙ QTL SUR 11p15.1 315 white VO2max 0.0014 (10, 150) QTL D13S153 13q14.2 204 white Trunk flexion 0.0002 (62)

QTL D13S175 13q11 90 blacks Wmax 0.0055 (150) ˙ QTL D13S787 13q12 315 white VO2max 0.0087 (150) QTL D13S796 13q33 351 white Wmax 0.0098 (150) ˙ QTL RADI 16q22 90 blacks VO2max 0.0041 (150) QTL D18S478 18q12 351 white Wmax 0.0064 (150) ˙ CKM 19q13.2 260 white VO2max 0.04 (156) ˙ QTL D20S857 20q13.1 90 blacks VO2max 0.0028 (150) ⌬ ˙ , response to an exercise training program; VO2max, maximal oxygen uptake; Wmax, maximal power output

Muscle Strength Phenotypes strength measures in women homozygous for the A allele compared with G/G homozygotes; these differences were Association studies. The studies reporting candidate not observed in men. Thomis and colleagues (184) stud- gene associations with muscle strength or anaerobic perfor- ied polymorphisms in both myostatin (GDF8) and ACE mance phenotypes are summarized in Table 5. In 2004, genes in relation to elbow flexor strength responses to seven studies reported data related to muscle strength phe- resistance training in 57 young men. Only one rare allele notypes. van Rossum and colleagues (200) reported the was observed for any of the four myostatin variants, significant association of the ER22/23EK polymorphism preventing analyses for that gene. For the ACE insertion/ within the glucocorticoid receptor gene (NR3C1) with arm deletion (I/D) polymorphism, no significant differences and leg muscle strength in men but not women. Arm and leg were observed for either baseline strength or the response strength was measured using arm pull dynamometry and of strength to resistance training. Hopkinson et al. (59) high jump, respectively. Grundberg et al. (47) examined two reported significantly higher knee extensor maximal polymorphisms (poly A repeat and BsmI) within the vitamin strength in COPD patients carrying the ACE D-allele D receptor gene (VDR) in relation to muscle strength in 175 compared with the I/I patients. This association was not women aged 20–39 yr. Greater hamstrings isokinetic mus- observed in 101 age-matched healthy controls. Finally, cle strength was reported in women homozygous for the Riechman and coworkers (151) reported no association shorter poly A repeat (ss) compared with women homozy- between the interleukin-15 receptor gene (IL15RA) and gous for the long poly A repeat (LL). Similar findings were the gain in arm or leg one-repetition maximum strength in reported for the BsmI variant (b and B alleles), reflecting the response to strength training in 153 young men and significant linkage disequilibrium between the s and B al- women. leles. No associations were reported for VDR genotype with quadriceps or grip strength. Roth et al. (160) reported significant associations with Linkage studies. the VDR FokI polymorphism (f and F alleles) and knee In 2004, two investigations provided linkage results rel- extensor isometric strength in 302 older Caucasian men. evant to muscle strength phenotypes (Table 4). Huygens et However, these associations were no longer significant al. (62) performed a linkage analysis in 329 young Cauca- once leg fat-free mass was accounted for in the models, sian male siblings from 146 families using a marker in the suggesting that the genotype-strength associations were retinoblastoma gene (RB1; D13S153) for trunk strength. explained by differences in muscle mass. Schrager and LOD scores between 1.62 and 2.78 (P Ͻ 0.002) were colleagues(166) examined the ApaI polymorphism (A/G) reported for trunk flexion measures with no evidence of of the insulinlike growth factor-2 (IGF2) gene in relation linkage for trunk extension phenotypes. In a second study, to muscle strength and power phenotypes in 485 men and Huygens and colleagues (61) performed a similar linkage women from the Baltimore Longitudinal Study of Aging. analysis for various measures of muscle mass and strength They reported significantly lower arm and leg isokinetic in the same young male cohort with microsatellite markers

HUMAN FITNESS GENE MAP 2004 Medicine & Science in Sports & Exerciseா 887 TABLE 5. Muscular strength and anaerobic phenotypes and association studies with candidate genes. Gene Location N Subjects Phenotype P Reference GDF8 2q32.2 286 Women 55 AA women Hip flexion 0.01 (169) (subsample of 286) Overall strength Ͻ0.01 (169) Hip flexion Ͻ0.01 Knee flexion Ͻ0.01 NR3C1 5q31 158 Men, 13–36 yr Arm strength Ͻ0.05 (200) Leg strength Ͻ0.05 CFTR 7q31.2 97 CF patients Peak anaerobic power Ͻ0.05 (170) CNTFR 9p13 465 KE ecc, sv Ͻ0.05 (158) KE ecc, fv Ͻ0.05 IGF2 11p15.5 397 Men aged 64–74 Grip strength 0.05 (163) 239 Women, 20–94 yr Arm peak torque con Ͻ0.05 (166) Arm peak torque ecc Ͻ0.05 Leg peak torque con sv Ͻ0.05 Leg peak torque con fv Ͻ0.05 CNTF 11q12.2 494 KE con, fv Ͻ0.05 (159) KE ecc, sv Ͻ0.05 KF con, sv Ͻ0.05 KF con, fv Ͻ0.05 KF ecc, sv Ͻ0.05 VDR 12q12-q14 501 PM women Grip and quadriceps strength Ͻ0.01 (43) 175 women, 2039 yr Knee flexion Ͻ0.05 (47) 302 men, Ͼ50 yr Knee extensor isometric torque Ͻ0.05 (160) COL1A1 17q21.3-q22.1 273 men (7186 yr) Grip strength 0.03 (199) Biceps strength 0.04 ACE 17q23 33 Muscle strength Ͻ0.05 (34) 83 PM women Specific muscle strength of adductor pollicis 0.017 (217) 103 COPD patients KE maximal strength Ͻ0.05 (59) KE twitch force Ͻ0.05 PM, postmenopausal; ⌬, training response; KE, knee extensor; KF, knee flexor; con, concentric; ecc, eccentric; sv, slow velocity (0.52 rad⅐sϪ1); fv, fast velocity (3.14 rad⅐sϪ1); AA, African-American; CF, cystic fibrosis. selected in the vicinity of 10 candidate genes from the the opposite relationship with ACE genotype, with ACE D myostatin pathway. Suggestive linkages were reported with homozygotes having lower O2 delivery than ACE I homozy- markers D2S118, D6S1051, and D11S4138 for knee exten- gotes. In all cases, ACE I/D heterozygotes had values inter- sion and flexion peak torque measures. These markers are mediate between the two homozygote groups. located within 12,000–680,000 base pairs of the myostatin McCole and coworkers (99) studied the hemodynamic (GDF8), cyclin-dependent kinase inhibitor 1A (CDKN1A), responses of postmenopausal women to submaximal and and myogenic factor 3 (MYOD1) gene loci, respectively maximal treadmill exercise. They found that the Gln27Glu (61). variant at the ADRB2 locus was independently associated

with only a-vDO2 during submaximal and maximal exer- HEALTH-RELATED FITNESS PHENOTYPES cise. The Trp64Arg ADRB3 variant did not independently associate with any hemodynamic responses to submaximal Hemodynamic Phenotypes or maximal exercise. Woods and colleagues (218) reported Acute exercise. Eisenach et al. (31) studied the effect that acute exercise -induced increase in plasma angiotensin of the Arg16Gly ADRB2 variant on hemodynamic responses converting enzyme and angiotensin II levels were not asso- ACE during handgrip exercise to fatigue in young, nonobese, ciated with the I/D genotype. normotensive men and women (Table 6). They found that peak heart rate at fatigue during the handgrip exercise was Gene–physical activity interactions significantly higher in Gly16 than Arg16 homozygotes (100 Ϯ 4vs93Ϯ 3 beats⅐minϪ1, P ϭ 0.001). Franks and coworkers (36) in a large population study Heled and coworkers (57) investigated the effect of the in England found that the inverse relationship usually ACE I/D gene polymorphism on the interindividual vari- evident between physical activity levels and blood pres- ability of hemodynamic responses to a 2-h exercise heat- sure was not present in carriers of the minor alleles, but tolerance test . They found that D/D homozygotes tended to was seen in common homozygotes at the G-62A and have a higher heart rate response at the end of the2hof C914T loci within the G-protein coupled receptor 10 exercise in a warm, humid environment than I allele carriers (GPR10) gene (Table 6). Haplotypes incorporating the (P ϭ 0.06). G-62A and C914T loci interacted with physical activity Kanazawa and coworkers (74) investigated the effect of levels to significantly associate with diastolic blood pres- the ACE I/D polymorphism on pulmonary hemodynamics sure (P ϭ 0.023) while tending to associate with systolic ϭ and O2 delivery during exercise in patients with COPD. blood pressure (P 0.08). They found that with exercise mean pulmonary arterial McCole and coworkers (99) studied the hemodynamic pressure and pulmonary vascular resistance were greater in responses of postmenopausal women ranging from seden-

ACE D than I homozygotes, whereas O2 delivery showed tary to endurance-trained athletes to submaximal and max-

888 Official Journal of the American College of Sports Medicine http://www.acsm-msse.org TABLE 6. Summary of the association studies between candidate gene markers and acute exercise-related hemodynamic phenotypes as well as gene–physical activity interactions on hemodynamic traits; genes causing exercise-related familial cardiac arrhythmias* are listed at the end of the table. Gene Location N Subjects Phenotype P Reference AMPD1 1p13 400 whites Maximal exercise SBP 0.003 (149) AGT 1q42-q43 25 Submaximal exercise DBP Ͻ0.01 (81)

190 sedentary white men DBPmax 0.007 (135) 61 PM women HRmax 0.008 (98) ADRB2 5q31-q32 232 HF patients Exercise cardiac index Ͻ0.05 (207) Exercise systemic vascular res. Ͻ0.05 Exercise stroke volume Ͻ0.05 12 obese women Exercise DBP 0.01 (93) 31 HR during handgrip exercise 0.001 (31) Ͼ EDN1 6p24.1 873372 with BMI 26 SBPmax 0.03 (186) Ͻ SBPmax 0.0001 GNB3 12p13 437 whites SBP at 50 W 0.036 (141) ˙ Ͻ ANG 14q11.1-q11.2 257 blacks SBP at 60% and 80% VO2max 0.05 (154) Ͻ SBPmax 0.05 ACE 17q23 58 Max heart rate Ͻ0.05 (52)

66 DBPmax 0.010 (37) 96 Exercise ANP 0.043 (38) 19 COPD patients Exercise Ppa Exercise Rpv 0.008 (72) Ͻ0.05 39 COPD patients Postexercise Ppa Ͻ0.01 (73) 62 PM women Submaximal exercise heart rate 0.04 (53) 37 COPD patients Postexercise Ppa Ͻ0.01 (70) 43 COPD patients Postexercise Rpv Ͻ0.01 (71) 33 COPD Exercise mPAP Exercise Rpv Ͻ0.05 (74) 0.001 ˙ Ͻ TGFB1 19q13.2 480 whites SBP at 50W, 60% VO2max 0.05 (155) Ͻ SBPmax 0.05 Gene–physical activity interactions

ADRB2 5q31-q32 62 PM women Submaximal exercise a-vDO2 0.05 (99) NOS3 7q36 63 FBFFVR 0.03 (24) 0.0003 832 Resting SBP 0.0062 (79) GPR10 10q26.13 687 men and women Resting DBP Resting SBP 0.006 (36) 0.008 Familial cardiac arrhythmias* CASQ2 1p13.3-p11 41 AR-FPVT Co-seg** (83) 29 AR-FPVT Co-seg** (129) RYR2 1q42.1-q43 2624 AD-FPVTAD- FPVT Co-seg** (84) Co-seg** (131) KCNQ1 11p15.5 Long QT syndrome 1 Co-seg** (209), See also ref. (168) for a review PM, postmenopausal; HF, heart failure; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; COPD, chronic obstructive pulmonary disease; Ppa, mean pulmonary artery pressure; Rpv, pulmonary vascular resistance; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; RPP, rate pressure product; BMI, body mass index; SV, stroke volume; Q, cardiac output; FBF, forearm blood flow; FVR, forearm vascular resistance; AR, autosomal recessive; AD, autosomal dominant; FPVT, familial polymorphic ventricular tachycardia. * Only familial cardiac arrhythmias where acute exercise has been shown to trigger cardiac event have been listed. ** Mutations cosegregate with the phenotype in affected families. imal treadmill exercise. They found that the Gln27Glu vari- Anthropometry and Body Composition ant at the ADRB2 locus interacted with habitual physical Phenotypes activity levels to significantly affect only a-vDO during 2 Association studies. Three studies reported signifi- submaximal exercise. The Trp64Arg variant of the ADRB3 cant associations between candidate genes and phenotypes did not interact with habitual physical activity levels to related to body composition in response to exercise (Table affect any hemodynamic responses to submaximal or max- 9). In one study, changes in percent body fat, fat mass, and imal exercise (99). trunk fat in response to 24 wk of endurance exercise were Training response. No new studies on the associations tested for associations with polymorphisms in the alpha-2B- between candidate genes and hemodynamic phenotype adrenergic receptor (ADRA2B), ADRB2, and ADRB3 genes training responses were published in 2004 (Table 7). in 29 sedentary men and 41 postmenopausal women (127). No association was found with the ADRA2B gene, but body fat changes were associated with variation in the ADRB2 Linkage studies and ADRB3 genes. The three adrenergic receptor gene in- No linkage studies pertaining to the response of hemodynamic teractions were also significant. A second study examined phenotypes to exercise were reported in 2004 (Table 8). whether polymorphisms in the cytochrome P450, family 19, Exercise and familial cardiac arrhythmias. No subfamily A, polypeptide (CYP19), and catechol-O-meth- new mutations underlying exercise-induced cardiac arrhyth- yltransferase (COMT) genes were associated with changes mias were reported in 2004. in body fatness after a year-long exercise intervention trial

HUMAN FITNESS GENE MAP 2004 Medicine & Science in Sports & Exerciseா 889 TABLE 7. Summary of the association studies between candidate gene markers and hemodynamic phenotype training responses. Gene Location N Cases Phenotype P Reference AMPD1 1p13 400 whites DBP at max 0.03 (149) AGT 1q42-q43 226 white males DBP at 50 W 0.016 (135) 120 males Resting SBP Ͻ0.01 (143) Resting DBP Ͻ0.01 TTN 2q31 SV and Q at 50 W 0.005 (140) NOS3 7q36 471 whites DBP at 50 W 0.0005 (142) HR at 50 W 0.077 RPP at 50 W 0.013 67 CAD patients APV response to acetylcholine Ͻ0.05 (32) LPL 8p22 18 Resting SBP Ͻ0.05 (50) Resting DBP Ͻ0.05 GNB3 12p13 163 black women Resting SBP 0.0058 (141) 255 blacks Resting DBP 0.032 473 whites HR at 50 W 0.013 HR at 50 W 0.053 SV at 50 W 0.012 BDKRB2 14q32.1-q32.2 109 white army recruits LV mass 0.009 (11) ACE 17q23 28 male soccer players LV mass 0.02 (33) 140 white army recruits Septal thickness 0.0001 (106) 49 white army recruits Posterior wall thickness 0.0001 End-diastolic diameter 0.02 LV mass 0.0001 LV mass index 0.0001 BNP Ͻ0.05 18 Resting DBP 0.005 (50) 294 white offspring HR at 50 W 0.0006 (135) 144 white army recruits LV mass 0.002 (115) 64 hypertensives Resting DBP Ͻ0.05 (221) Resting MAP Ͻ0.05 APOE 19q13.2 18 Resting SBP Ͻ0.05 (50) PPARA 22q13.31 144 white army recruits LV mass 0.009 (64) SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; RPP, rate pressure product; SV, stroke volume; Q, cardiac output; BNP, brain natriuretic peptide; LV, left ventricular; MAP, mean arterial pressure; APV, average peak velocity. in 173 postmenopausal women (197). One polymorphism in In a second study, polymorphisms in the leptin (LEP) the CYP19 gene was associated with greater reductions in and leptin receptor (LEPR) genes were tested for associ- BMI, percent body fat, and fat mass, whereas one polymor- ation with glucose homeostasis in response to endurance phism in the COMT gene was associated with a smaller exercise in 397 men and women from the HERITAGE decrease in percent body fat. The third study examined the Family Study (85). The LEPR K109R, Q223R, and contribution of polymorphisms in the IL15RA gene in mus- K656N polymorphisms were associated with exercise- cle phenotype responses to 10 wk of resistance exercise induced changes in various measures of insulin sensitiv- training in 153 men and women (151). Polymorphisms in ity and glucose homeostasis. A polymorphism in the LEP the exon 4 and the untranslated region of exon 7 of the gene (A19G) was also found to be associated with exer- IL15RA gene were associated with muscle mass response to cise-induced changes in fasting insulin. A third study exercise and explained 7.1 and 3.5% of the gains in lean examined the influence of the interleukin 6 (IL6) 174G/C body mass, respectively. The IL15RA poylmorphism was polymorphism on changes in various indicators of glu- also associated with changes in leg and arm circumferences cose tolerance after 24 wk of aerobic exercise in 56 men (151). and women (101). The training-induced changes in glu- Linkage studies. No linkage studies pertaining to the cose area under the curve were significantly associated response of body composition to exercise training were with the IL6 polymorphism, whereas no association was reported in 2004 (Table 10). found with training-induced changes in other indicators Insulin and glucose metabolism phenotypes. A total of four studies reported associations between candidate of glucose tolerance and body fatness. Finally, a poly- genes and the response of glucose and/or insulin metabolism morphism in the promoter of the hepatic lipase (LIPC) phenotypes to exercise (Table 11). The effects of the gene was investigated for its association with the inci- Gln27Glu and Arg16Gly polymorphism of the ADRB2 gene dence of Type 2 diabetes in 522 subjects with impaired on glucose metabolism was investigated in 124 Japanese glucose tolerance (IGT) randomized to either an inter- men who participated in a 3-month exercise program of low vention (detailed advices on diet and exercise to reduce to moderate intensity (65). No association was found with body weight) group (N ϭ 248) or a control group (187). the metabolic characteristics at baseline, but changes in A significant interaction was found between the LIPC fructosamine levels, an indicator of the average blood glu- polymorphism and the study group (P ϭ 0.024), which cose levels over the past 2–3 wk, were greater in the Glu resulted in a significant effect of the polymorphism in the allele carriers than in the noncarriers (P ϭ 0.0005). No rate of conversion from impaired glucose tolerance to association was found between the two ADRB2 polymor- Type 2 diabetes in the intervention group but not in the phisms and changes in body fatness. control group.

890 Official Journal of the American College of Sports Medicine http://www.acsm-msse.org TABLE 8. Exercise-related hemodynamic phenotypes and linkage studies. Gene Marker Location N Pairs Phenotype P Reference QTL D1S1588, D1S1631 1p21.3 102 black SV at 50 W 0.005 (133) QTL D1S189, CASQ2 1p13-p21 42 members from 7 families AR-FPVT Lod ϭ 8.24 (82, 83) ˙ QTL D2S2952 2p24 344 white SBP at 80% VO2max 0.0026 (134) QTL D2S1400 2p22-p25 102 black DBP at 50 W 0.0044 (134) ˙ QTL D2S1334 2q21 344 white SBP at 80% VO2max 0.0031 (134) QTL D2S148, D2S384 (TTN) 2q31 328 white SV and Q at 50 W 0.0002 (140) QTL D2S364 2q31-q32 52 members from 2 families (14 affected) Abnormal PASP response to exercise Lod ϭ 4.4 (48) QTL D5S640 5q31-q33 344 white DBP at 50 W 0.0046 (134) ˙ QTL D6S1270 6q13-q21 344 white DBP at 80% VO2max 0.0037 (134) QTL D6S2436 6q24-q27 344 white DBP at 50 W 0.0041 (134) ˙ QTL D7S2195 7q35 102 black SBP at 80% VO2max 0.0046 (134) QTL D8S373 8q24.3 344 white SBP at 50 W 0.0005 (134) QTL D9S58, 106, 934 9q32-q33.3 328 white SV at 50 W 0.003 to 0.006 (133) QTL D10S2325 10p14 102 black Q at 50 W 0.0045 (133) QTL D10S1666 10p11.2 328 white SV at 50 W 0.00005 (133) ˙ QTL D10S2327 10q21-q23 102 black DBP at 80% VO2max 0.0019 (134) ˙ QTL D10S677 10q23-q24 344 white SBP at 80% VO2max 0.0018 (134) QTL D11S2071 11p15.5 102 black DBP at 50 W 0.0042 (134) ˙ QTL UCP3 11q13 102 black DBP at 80% VO2max 0.0023 (134) ˙ QTL D12S1301 12p12-p13 102 black SBP at 80% VO2max 0.005 (134) QTL D12S1724 12q13.2 102 black SV at 50 W 0.0038 (133) QTL D13S250 13q12 91 black Resting SBP 0.004 (148) ˙ QTL D14S283 14q11.1-q12 344 whites SBP at 80% VO2max 0.0034 (134) QTL D14S53 14q31.1 328 whites SV at 50 W 0.0019 (133) ˙ QTL D15S211 15q24-q25 344 whites DBP at 80% VO2max 0.0024 (134) ˙ QTL D15S657 15q26 102 blacks SBP at 80% VO2max 0.0035 (134) ˙ QTL D16S261 16q21 344 white SBP at 80% VO2max 0.0026 (134) ˙ QTL D17S1294 17p11-q11 102 blacks SBP at 80% VO2max 0.0031 (134) QTL D18S843 18p11.2 102 blacks DBP at 50 W 0.0012 (134) QTL D18S866 18q11.2 102 blacks Q at 50 W 0.0022 (133) ⌬ ˙ , response to an exercise training program; VO2max, maximal oxygen uptake; LOD, logarithm of odds; PASP, pulmonary artery systolic pressure; AR-FPVT, autosomal recessive familial polymorphic ventricular tachycardia; SV, stroke volume; SBP, systolic blood pressure; DBP, diastolic blood pressure; Q, cardiac output.

No linkage studies pertaining to the responses of insulin class. White women with an APOE 4/4 genotype exhib- and glucose metabolism phenotypes to exercise training ited dramatic decreases in and somewhat were reported in 2004 (Table 12). smaller decreases in apo AI and HDL2-C and an increase Blood lipid and lipoprotein phenotypes. In 2004, in LDL-C, whereas women with a 2/4 genotype experi- four new papers were published that included lipid re- enced changes in the opposite direction for all of these sponses to acute or chronic exercise and/or physical activity measures. In contrast to white women, the only lipid- (Table 13). Woo et al. (215) investigated the association related measure showing a significant difference by between variation in the apolipoprotein C-III (APOC3) gene APOE genotype after exercise in black women was in apo and plasma lipid response after6dofacute submaximal AI levels, which decreased for individuals with a 2/4 aerobic exercise in 100 Korean men. Individuals with a genotype but increased in all other genotype classes. S2/S2 genotype had significantly higher (TG) White men were the only group that experienced a sig- levels at baseline and significantly greater decreases in TG nificant change in TC levels by APOE genotype after after exercise (after adjustment for baseline values) com- exercise, with individuals carrying an E2 allele showing pared with S1/S1 or S1/S2 genotypes. Measures of total decreased TC and individuals with 3/3, 3/4, or 4/4 geno- (TC), high density lipoprotein (HDL)-choles- types showing increased levels of TC after exercise train- terol (HDL-C), low-density lipoprotein (LDL)-cholesterol ing. No other race or gender group demonstrated any (LDL-C), glucose, and insulin were not different by geno- significant exercise-related change in TC by APOE ge- types either before or after acute exercise (215). notype. White men also demonstrated significant APOE- Leon et al. (89) studied the effect of apolipoprotein E related changes in LDL-C, VLDL-C, and apolipoprotein (APOE) genotype on lipid responses after 3 d·wkϪ1 ex- B (apo B) levels. The most dramatic differences in lipid ercise training for 20 wk in a family-based cohort of values in the white men were for triglycerides, in which white and black men and women from the HERITAGE the 2/2, 2/3, 3/3, and 3/4 genotype classes exhibited study. Distinct race and gender differences in exercise substantial decreases after exercise but individuals with a training lipid response by APOE genotype were observed. 4/4 genotype experienced a large gain in triglyceride Of all race and gender groups, white women experienced levels. The only significant APOE-related change after the greatest number of APOE-related changes after exer- exercise in black men was in LDL-C, in which individ- cise, with significant changes by genotype for LDL-C, uals with a 2/3 or 2/4 genotyped showed decreases and HDL-C, HDL-C fractions, VLDL cholesterol, triglycer- those with a 3/3, 3/4, or 4/4 genotype showed increases in ides, and apolipoprotein AI (apo AI) levels. The greatest LDL-C (89). differences in lipid changes after exercise were generally In a study by Thompson et al. (185), the association between the 2/* genotype classes versus the 4/4 genotype between APOE genotype and serum after chronic

HUMAN FITNESS GENE MAP 2004 Medicine & Science in Sports & Exerciseா 891 TABLE 9. Evidence for the presence of associations between candidate genes and the response of BMI, body composition, or fat distribution phenotypes to habitual physical activity or regular exercise. Gene Location N Cases Phenotype P Reference Interactions with exercise/ physical activity GDF8 (MSTN) 2q32.2 18 men and 14 women Leg muscle volume NS (all) 0.067 (women) (63) ADRB2 5q31-q32 420 men Weight 0.0001 (102) BMI 0.0001 Waist circumference 0.0001 Hip circumference 0.0007 WHR 0.02 252 women Obesity, BMI 0.005 Ͻ P Ͻ 0.05 (22) NPY 7p15.1 9 Leu7/Leu7 and Plasma NPY during exercise Ͻ0.05 (68, 69) 9 Leu7/Pro7 Plasma GH during exercise Ͻ0.05 ADRB3 8p12-p11.2 61 obese diabetic women Weight Ͻ0.001 (161) BMI Ͻ0.001 WHR Ͻ0.001 UCP3 11q13 368 obese patients BMI 0.015 (122) VDR 12q12-q14 33 women Bone mineral density 0.03 (195) 120 girls Bone mineral density 0.04 (80) 99 girls Bone mineral density 0.02 (92) 575 PM women Bone mineral density 0.04 (8) 44 male athletes; 44 controls Bone mineral content; bone mineral volume Ͻ0.02 (116) Training responses or acute exercise PPARG 3p25 490 subjects Body weight 0.04 (90) ADRB2 5q31-q32 12 obese women RER Ͻ0.05 (93) 482 men and women BMI, FM, %FAT, subcutaneous fat 0.0003 Ͻ P Ͻ 0.03 (41) 70 men and women Percent body fat, trunk fat Ͻ0.02 (127) ESR1 6q25.1 140 men Bone mineral density 0.007 (146) LPL 8p22 249 white women BMI, fat mass, percent body fat 0.01 Ͻ P Ͻ 0.05 (40) 171 black women Abdominal visceral fat 0.05 ADRB3 8p12-p11.2 106 men Leptin Ͻ 0.05 (67) 76 women Body weight, BMI, waist circumference 0.001 Ͻ P Ͻ 0.02 (174) 70 men and women Fat mass, percent body fat, trunk fat Ͻ0.05 (127) IL6 7p21 130 men Cortical bone area 0.007 (29) IL15RA 10p15-p14 153 men and women Lean mass Ͻ0.05 (151) Arm circumference Ͻ0.05 Leg circumference Ͻ0.05 UCP3 11q13 503 whites Subcutaneous fat 0.0006 (88) GNB3 12p13 255 blacks FM 0.012 (141) %FAT 0.006 VDR 12q12-q14 20 men 1,25 dihydroxyvitamin D3 plasma level Ͻ0.05 (182) IGF1 12q22-q23 502 men and women Fat-free mass 0.005 (179) CYP19A1 15q21.1 173 women BMI, fat mass, percent body fat Ͻ0.05 (197) PNMT 17q21-q22 149 women Body weight 0.002 (126) ACE 17q23 81 men Body weight 0.001 (105) Fat mass 0.04 Fat-free mass 0.01 COMT 22q11.21-q11.23 173 women Percent body fat Ͻ0.05 (197) BMI, body mass index; WHR, waist-to-hip ratio; GH, growth hormone; RER, respiratory exchange ratio; FM, fat mass; %FAT, percent body fat. exercise was assessed in healthy sedentary subjects who APOE 3/4 subjects experiencing slight increases in these underwent 6 months of 4 d·wkϪ1 aerobic exercise training. values after exercise training. Surprisingly, measures of After adjustment for baseline values, BMI, and age, APOE total cholesterol, triglycerides, LDL-cholesterol, APOB, genotype was significantly associated with TC/HDL, LDL/ HDL-cholesterol fractions, Apo AI, and postheparin hepatic HDL, and ApoB/AI ratios, with APOE 2/3 and 3/3 subjects triglyceride lipase were not different among APOE geno- experiencing small decreases in each of these values and type groups in the total cohort either before or after exercise.

TABLE 10. Summary of linkage studies with training-induced changes in body composition phenotypes. Gene Marker Location N Pairs Phenotype P Reference QTL S100A1 1q21 291 white FFM 0.0001 (19) ATP1A2 1q21-q23 291 white %FAT 0.001 (19) QTL S100A1, ATP1A2, ATP1B1 1q21-q23 72 black ATF Ͻ0.01 (147) QTL D1S1660 1q31.1 291 white FM, %FAT 0.0007 (19) QTL D5S1725 5q14.1 291 white BMI 0.0004 (19) QTL D7S3070 7q36 72 black ATF 0.00032 (147) QTL D9S282 9q34.11 291 white FM, %FAT, sum of skinfolds 0.001 Ͻ P Ͻ 0.04 (19) QTL ADRA2A 10q24-q26 72 black ASF Ͻ0.01 (147) QTL IGF2 11p15.5 72 black ATF Ͻ0.01 (147) QTL UCP2 11q13 291 white %FAT 0.0008 (19) FM 0.004 (88) IGF1 12q22-q23 308 white FFM 0.0002 (179) QTL IGF1 12q22-q23 291 white FFM 0.0001 (19) QTL D18S878, 1371 18q21-q23 291 white FM, %FAT 0.001 Ͻ P Ͻ 0.04 (19) QTL, human quantitative trait locus identified from a genome scan; FFM, fat-free mass; FM, fat mass; %FAT, percent body fat; ATF, total abdominal fat; ASF, abdominal subcutaneous fat.

892 Official Journal of the American College of Sports Medicine http://www.acsm-msse.org TABLE 11. Evidence for the presence of associations between candidate genes and the responses of glucose and insulin metabolism phenotypes to habitual physical activity or regular exercise. Gene Location N Subjects Phenotype P Reference Interactions with exercise/physical activity VDR 12q12-q14 1539 subjects Fasting glucose Ͻ0.001 (119) Training responses or acute exercise PPARG 3p25 123 men Fasting insulin, HOMA 0.02 Ͻ P Ͻ 0.05 (66) UCP1 4q28-q31 106 men Fasting glucose Ͻ0.01 (67) ADRB2 5q31-q32 19 obese women Insulin to glucose ratio Ͻ0.05 (94) 124 men Fructosamine 0.0005 (65) ADRB3 8p12-p11.2 106 men Fasting glucose, glycosylated hemoglobin levels Ͻ0.05 (161) LEPR 397 men and women Insulin sensitivity, glucose tolerance, pancreatic B-cell 0.01 Ͻ P Ͻ 0.05 (85) compensation for insulin resistance LEP 397 men and women Fasting insulin 0.02 (85) IL6 7p21 56 men and women Glucose tolerance 0.02 (101) LIPC 15q21-q23 522 subjects Incidence of Type 2 diabetes 0.001 (187) ACE 17q23 35 men Insulin sensitivity Ͻ0.05 (27)

Lipoprotein lipase levels were significantly different among interleukin-1. Resistance exercise has been reported to associ- women only (N ϭ 60) in the Thompson study (185), with ate with of IL-1beta, IL-6, and tumor necrosis subjects with APOE 3/3 genotype exhibiting decreased lev- alpha depending on IL-1beta genotype (28). els and 2/3 and 3/4 genotypes showing increased levels of Riechman et al. (152) investigated the association be- the enzyme. Mukherjee et al. (111) reported a significant tween a GϾA polymorphism in the 3= region of the steroid interaction between variation within the cholesteryl ester sulfatase (STS) gene and changes in plasma dehydropedi- transfer protein (CETP) gene and physical activity in pre- androsterone (DHEA) and its sulfated conjugate, DHEAS, dicting serum HDL-C levels in coronary artery disease levels after resistance exercise and training. The investiga- (CAD) patients and healthy controls (N ϭ 390 males, N ϭ tors reported that carriers of the G allele experienced sig- 114 females). In CAD cases only, active men and women nificantly greater increases in DHEA after acute and chronic (those who exercised the equivalent of an h daily walk) with exercise and DHEA/DHEAS ratio after chronic exercise a B1/B1 genotype had significantly higher HDL cholesterol only, compared with A/A homozygotes for the STS gene levels compared with individuals with B1/B2 or B2/B2 (152). genotypes, regardless of activity level. This association was Chronic diseases. Slattery and colleagues (177) in- also found in all 2- and 3-vessel CAD cases (but not 1-ves- vestigated the interactions between physical activity and sel) and in individuals with a previous myocardial infarction vitamin D receptor (VDR) gene polymorphisms on the risk (111). of colon and rectal cancers in two case-control cohorts. Hemostatic factors, inflammation phenotypes, There was a significant interaction between physical activity and plasma hormone levels. Aerobic exercise training and the Fok1 polymorphism of the VDR gene on the colon ˙ for six months, which led to a 24% increase in VO2max, was cancer risk. Sedentary ff homozygotes had over threefold associated with a statistically significant decrease in plasma increased risk and physically active FF homozygotes had coagulation factor VII antigen level in middle-aged men and over twofold increased risk of developing colon cancer women. However, the change was unrelated to coagulation compared with the ff homozygotes who reported high levels factor VII gene polymorphisms [(Ϫ323 (0/10 bp/401 (G/T) of physical activity (177). haplotype or Ϫ402 G/A) genotype.]. On the other hand, Exercise intolerance. Four studies reporting four new factor VII antigen changes associated with apolipoprotein E genes related to exercise intolerance were published in 2004 genotype as well as with ATPase binding cassette-1 geno- (Table 14). Hellerud and coworkers (58) reported a 20-yr type (44). follow-up study of two boys with glycerol kinase (GK) C-reactive protein (CRP), a marker of chronic low-grade deficiency due to a deletion of exon 17 and an A/G mutation inflammation, has been shown to be inversely associated with in exon 7 of the GK gene. Both subjects showed pronounced physical activity. Training (118) or strenuous exercise (13) exercise intolerance in childhood. However, the exercise- -induced changes in plasma CRP levels appear, however, to be related symptoms, as well as symptoms invoked by fasting, independent of genetic polymorphisms at the CRP gene loci. had disappeared when the subjects were retested at 23 and On the other hand, plasma CRP is induced by IL-6, which in 31 yr of age (58). Pantoja-Martinez and colleagues (123) turn is partly regulated by another pro-inflammatory cytokine, reported a case study of a 7-yr-old boy suffering from intense muscle pain after physical exercise. Myalgia coin- TABLE 12. Insulin and glucose metabolism phenotypes and linkage studies. cided with greatly elevated (16 times normal) creatine ki- Gene Markers Location N Pairs Phenotype P Reference nase levels, which were normalized at rest. Adenosine QTL D2S1776 2q31 300 white f-Insulin 0.0042 (86) monophosphate deaminase (AMPD1) deficiency was con- QTL PON2 7q21 300 white f-Insulin 0.0035 (86) firmed from skeletal muscle biopsy. DNA analysis identi- QTL LEP 7q31 300 white f-Insulin 0.0004 (86) QTL UCP3 11q13 300 white f-Insulin 0.0097 (86) fied the boy to a homozygote for the Q12X nonsense mu- QTL D15S63 15q11 72 black f-Insulin 0.0059 (86) tation in exon 2 of the AMPD1 gene leading to a truncated ⌬, response to an exercise training program; f, fasting. and inactive form of the enzyme (123).

HUMAN FITNESS GENE MAP 2004 Medicine & Science in Sports & Exerciseா 893 TABLE 13. Blood lipid, lipoprotein, hemostatic, inflammation, and steroid phenotypes and association studies with candidate genes. Gene Location N Subjects Phenotype P Reference Acute exercise FGB 4q28 149 Fibrinogen 0.01 (107) ADRB2 5q31-q32 15 obese women Lipolysis, fat oxidation Ͻ0.05 (95) 19 obese women Fat oxidation 0.024 (94) NPY 7p15.1 18 Serum FFA Ͻ0.05 (68) APOC3 11q23.1-q23.2 100 Korean men Triglycerides 0.042 (215) STS Xp22.32 62 men, 58 women DHEA 0.006 (152) Exercise training FGA 4q28 125 Fibrinogen 0.002 (145) FGB 4q28 250 Fibrinogen 0.001 (12) SERPINE1 7q21.3-q22 132 Plasminogen activator inhibitor, type-1 0.025 (198) LPL 8p22 18 HDL-cholesterol Ͻ0.05 (50) HDL2-cholesterol Ͻ0.05 CETP 16q21 32 HDL3-5NMR-cholesterol Ͻ0.05 (212) LIPG 18q21.1 83 HDL-cholesterol 0.04 (54) APOE 19q13.2 51 HDL-cholesterol Ͻ0.03 (51) HDL2-cholesterol Ͻ0.01 252 white women LDL-cholesterol 0.022 (89) HDL-chol. 0.0062 (89) HDL2-chol. 0.013 (89) HDL3-chol. 0.013 (89) VLDL-chol. Ͻ0.0001 (89) Triglycerides 0.0024 (89) apoA-I Ͻ0.0001 (89) 241 white men Total chol. Ͻ0.0001 (89) LDL-chol. Ͻ0.0001 (89) HDL-chol. 0.05 (89) Triglycerides 0.011 (89) apoB 0.005 (89) 177 black women apoA-I 0.043 (89) 89 black men LDL-chol. 0.017 (89) 120 men and women TC/HDL ratio 0.033 (185) LDL/HDL 0.015 (185) ApoB/AI 0.046 (185) 60 women LPLA 0.032 (185) STS Xp22.32 62 men, 58 women DHEA 0.005 (152) DHEA:DHEAS 0.022 Exercise-genotype interactions APOA2 1q21-q23 200 Serum triglycerides Ͻ0.05 (128) FGA 4q28 159 Fibrinogen 0.024 (144) ADRB2 5q31-q32 604 Nonesterified FFA 0.05 (103) PON1 7q21.3 256 Serum triglycerides 0.017 (172) HDL cholesterol 0.018 17 PON1 activity Ͻ0.001 (188) Oxidized LDL 0.018 LPL 8p22 379 Serum cholesterol 0.003 (9) apolipoprotein 0.003 BHDL-cholesterol 0.03 LIPC 15q21-q23 200 HDL-cholesterol Ͻ0.01 (128) Ͻ0.01 CETP 16q21 52 Male CAD cases HDL-cholesterol 0.007 (111) 15 Female CAD cases HDL-cholesterol 0.029 (111) APOE 19q13.2 713338 Serum cholesterol 0.014 (181) (23) LDL-cholesterol 0.0082 HDL/ serum cholesterol 0.0004 HDL cholesterol 0.001 1708 HDL-cholesterol 0.001 Ͻ P Ͻ 0.008 (7) Triglycerides 0.03 200 LDL-cholesterol Ͻ0.01 (128) Ͻ0.01 HDL, high-density lipoprotein; LDL, low-density lipoprotein; FFA, free fatty acids.

Three novel mutations in the sarcoglycan gamma gene patient (201). McFarland et al. (100) reported a reexamina- (SGCG) were reported in two Turkish and one Moroccan tion of an exercise intolerance patient, whose symptoms males with limb-girdle muscular dystrophy type 2C (201). were initially attributed to a mutation in the mitochondrial All patients had experienced progressive walking distur- tRNA(Phe) gene (MTTF). However, resequencing of the bances, exercise intolerance, and leg pains for several years, patient’s entire mitochondrial DNA revealed that the true and clinical examination confirmed the limb-girdle weak- pathogenic mutation wasaTtoCsubstitution in the cyto- ness and calf hypertrophy. DNA sequence analysis identi- chrome c oxidase subunit 2 (MTCO2) gene, which changes fied a homozygous splice site mutation in exon 5 in the the encoded amino acid from leucine to proline in a highly Turkish brothers, whereas a homozygous nonsense mutation conserved region of the enzyme. Considering the high mu- in exon 2, which replaces a tryptophan residue at codon 31 tation rate in the mitochondrial genome, these data empha- by a premature stop codon, was found in the Moroccan size the importance of the whole mitochondrial genome

894 Official Journal of the American College of Sports Medicine http://www.acsm-msse.org TABLE 14. Genes encoded by nuclear and mitochondrial DNA in which mutations cGMP-dependent protein kinase (PKG) (121). PKG activity is have been reported in patients with exercise intolerance. significantly higher in wild-type rovers than in wild-type and Gene OMIM No. Location Reference mutant sitters and activation of the dg2 gene reverts foraging Nuclear DNA CPT2 255110 1p32 (97, 180, 183, 204, 205) behavior from a sitter to a rover. Furthermore, overexpression AMPD1 102770 1p13 (123) of the dg2 gene in sitters changed their behavior to the rover PGAM2 261670 7p13-p12 (49, 189, 194) phenotype (121). LDHA 150000 11p15.4 (191) PYGM 232600 11q12-q13.2 (192) Association studies. Only a few association studies PFKM 232800 12q13.3 (173, 190, 206) on DNA sequence variation in candidate genes and physical SGCG 253700 13q12 (201) ENO3 131370 17pter-p11 (21) activity traits are available (Table 15). The candidate genes ACADVL 201475 17p13-p11 (165) with positive findings include DRD2, ACE, LEPR, calcium- SGCA 600119 17q21 (104) sensing receptor (CASR), and aromatase (CYP19A1). The GK 307030 Xp21.3 (58) PHKA1 311870 Xq12-q13 (14) first three genes were investigated with an a priori hypoth- PGK1 311800 Xq13 (193) esis on the association between physical activity and DNA Mitochondrial DNA MTTL1 590050 3230–3304 (17) sequence variation (175,178,213). In the other studies, the MTND1 51600 3307–4262 (113) activity traits were treated as covariates in association anal- MTTI 590045 4263–4331 (18) yses focusing on other target traits (bone mineral density MTTM 590065 4402–4469 (202) MTTY 590100 5826–5891 (132) (BMD)) (91,162). MTCO1 516030 5904–7445 (75) Simonen and coworkers (175) investigated the associations MTTS1 590080 7445–7516 (46) MTCO2 516040 7586–8269 (100) between physical activity phenotypes and DNA sequence vari- MTTK 590060 8295–8364 (112) ation in the DRD2 gene locus in the Que´bec Family Study MTCO3 516050 9207–9990 (55) MTND4 516003 10760–12137 (6) (QFS) and the HERITAGE Family Study subjects. In both MTTL2 590055 12266–12336 (76, 203) cohorts, a C/T transition in codon 313 of the gene was asso- MTTE 590025 14674–14742 (56) ciated with physical activity levels in white women. The T/T MTCYB 516020 14747–15887 (3–5, 15, 77, 87, 96, 167) homozygote women of the QFS reported significantly less OMIM, Online Medelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?dbϭOMIM). weekly activities during the previous yr than the heterozygotes and the C/C homozygotes. Similarly, among the white women of the HERITAGE Family Study, the T/T homozygotes sequencing in the detection of causal mutations for mito- showed lower sports and work indices derived from the ARIC- chondrial disorders (100). Baecke questionnaire than the other genotypes. No associa- Physical activity. The previous editions of the Human tions were found in males or in black women (175). In Pima Fitness Gene map have focused exclusively on physiologi- Indians, a glutamine (Gln) to arginine (Arg) substitution in cal and biological traits in the context of acute and chronic codon 223 of the LEPR gene was associated with total physical exercise. This year we are incorporating for the first time a activity, calculated by dividing 24-h energy expenditure by section on genes and physical activity (behavior). Although sleeping energy expenditure measured in a respiratory cham- both environmental and social factors have major influence ber. The Arg233Arg homozygotes showed about 5% lower on the habitual physical activity levels, both twin and family physical activity level than the Gln223Gln homozygotes (178). studies support the notion that genetic factors are also in- Winnicki et al. (213) investigated the determinants of volved. Studies in monozygotic (MZ) and dizygotic (DZ) habitual physical activity level in a group of never-treated twins have consistently reported greater intraclass correla- stage I hypertensives. Physical activity was assessed by a tions for activity traits in MZ than in DZ twins. Likewise, questionnaire and the subjects were classified as sedentary family studies have reported greater between family than or exercisers (leisure or sports activities at least once a week within family variance in phenotypes reflecting physical during the previous 2 months). The ACE I/D genotype, age, activity and sedentarism. Heritability estimates have ranged sex, marital status, profession, and coffee and alcohol con- from 30 to 83% in twin studies and from 10 to 30% in sumption were included as predictors of physical activity studies with nuclear families. level in the regression model. The ACE genotype and mar- Data on molecular genetics of physical activity levels in ital status were the strongest contributors to physical activity humans are still scarce. However, animal studies provide sev- status. The frequency of the D/D genotype was significantly eral examples how genes may affect physical activity patterns. higher in the sedentary group than among active subjects For example, mice lacking the dopamine transporter gene approximately 76% of the D/D homozygotes were seden- exhibit marked hyperactivity (39), whereas dopamine receptor tary, whereas the corresponding frequency in the I-allele D2 (DRD2) deficient mice are characterized by reduced phys- homozygotes was 48% (213). ical activity levels (78). Another example of the potential Lorentzon and colleagues (91) investigated the associa- involvement of a gene in physical activity regulation comes tions between the CASR gene polymorphism and BMD and from the fruit fly (Drosophila melanogaster). These insects its predictors, including habitual physical activity, in ado- exhibit two distinct activity patterns related to food-search lescent Swedish girls. The weekly amount of weight-bearing behavior; rovers move about twice the distance while feeding physical activity during the previous year was estimated compared with sitters. This activity pattern is genetically de- using a standardized questionnaire, and a G/T transversion termined and is regulated by the dg2 gene, which encodes a in codon 986 inducing an alanine to serine substitution was

HUMAN FITNESS GENE MAP 2004 Medicine & Science in Sports & Exerciseா 895 TABLE 15. Association and linkage studies for physical activity phenotypes. Table 16. Evolution in the status of the human gene map for performance and Gene/ N Subjects/ health-related fitness phenotypes. Marker Location Sib-Pairs Phenotype P Reference Phenotypes 2000 2001 2002 2003 2004 Associations Endurance LEPR 1p31 268 Total physical activity 0.008 (178) No. of papers 20 24 29 39 47 (24-h EE / sleeping No. of loci 22 23 25 31 37 EE) Strength ϩ anaerobic CASR 3q21-q24 97 Weight-bearing physical 0.01 (91) No. of papers 268916 activity No. of loci 257813 DRD2 11q23 402 white women Physical activity 0.016 (175) Hemodynamics 256 white women Sports index 0.023 (175) No. of papers 12 18 28 35 40 Work index 0.004 No. of loci 7 31 45 46 47 CYP19A1 15q21.1 331 Physical activity 0.039 (162) Familial cardiac arrhythmias ACE 17q23 355 Sedentary vs. active 0.001 (213) No. of papers — —666 No. of loci — —555 Linkage Anthropometry ϩ body composition D2S2347 2p22.3 309 Inactivity 0.0012 (176) No. of papers 7 15 25 30 33 UCP1 4q28-q31 309 Moderate to strenuous 0.005 (176) No. of loci 7 21 28 31 34 activity Insulin ϩ glucose metabolism IGFBP1 7p13-p12 308 Inactivity 0.0046 (176) No. of papers 124711 308 Moderate to strenuous 0.006 (176) No. of loci 1 1 3 11 15 activity Lipids, inflammation ϩ hemostatics D9S938 9q31 308 Moderate to strenuous 0.0028 (176) No. of papers 8 11 16 20 25 activity No. of loci 5 7 8 11 14 C11P15_3 11p15 329 Total activity (previous 0.0089 (176) Chronic disease year) No. of papers — — — 3 4 D13S317 13q22 308 Total activity 0.0029 (176) No. of loci — — — 4 5 308 Moderate to strenuous 0.0067 (176) Exercise intolerance activity No. of papers — 30 36 39 43 D15S165 15q13 329 Total activity (previous 0.009 (176) No. of loci — 20 22 23 27 year) Physical activity PLCG1 20q12 308 Inactivity 0.0074 (176) No. of papers ———— 5 No. of loci ————13

genotyped with a polymerase chain reaction–restriction Summary and Conclusions fragment length polymorphism method. Carriers of the serine allele reported about 1.4 h less physical activity per This review provides a compendium of all genes and markers that have been associated with performance and week than the homozygotes for the alanine allele (91). In health-related fitness phenotypes in scientific papers pub- postmenopausal Finnish women, a TTTA repeat in intron 4 lished by the end of 2004. Even those who know little about of the CYP19A1 gene was not associated with BMD, frac- molecular biology realize that exciting advances have been ture risk, or circulating estradiol levels (162). Physical ac- made in the understanding of the molecular and cellular tivity was the only predictor of bone health that was asso- regulation of the adaptation to activity and inactivity in the ciated with the CYP19A1 genotype. The proportion of last decade. These advances have been recently summarized physically active persons, defined as 3 or more hours of in a book entirely devoted to this topic (110). Although we physical activity per week, was 36.6, 25.7, and 19.6% in have a long way to go, we are beginning to understand women with short, midsize, and long TTTA repeats, respec- which genes and pathways are contributing to the response tively (162). of various tissues and organs to acute or repeated exposures Linkage studies. The first genomewide linkage scan to exercise or muscle contractions. These studies are of for physical activity traits was carried out in the Que´bec paramount importance if we are to understand the true Family Study cohort (176). The scan was based on 432 biological determinants of physical performance and of the polymorphic markers genotyped in 767 subjects from 207 role of regular exercise in disease prevention or of physical families. Physical activity measures were derived from a 3-d inactivity in common chronic diseases and premature death. activity diary (total daily activity, inactivity, moderate to In contrast, little progress has been made with respect to strenuous activity) and an 11-item questionnaire (weekly the genetic basis of human variation in performance and physical activity during the past year). The strongest evi- health-related fitness. Indeed, although a growing number of dence of linkage (P ϭ 0.0012) was detected on chromosome genes are being identified, only a handful of them have been 2p22-p16 with the physical inactivity phenotype. Sugges- investigated with a view to assess whether DNA sequence tive linkages were also found on 13q22 with total daily variation in such genes play a role in the biological basis of activity and moderate to strenuous activity phenotypes, and human individuality. The latter is a topic that has received on 7p11 with both inactivity and moderate to strenuous only very limited attention to date. The current stagnation on activity (Table 15). In addition, weekly activity during the the genetic front needs to benefit from the advances that are taking place in the broader field of the molecular and cel- past yr showed suggestive evidence of linkage on 11p15 and lular biology of exercise. 15q13, inactivity on 20q12, and moderate to strenuous ac- The 2004 map includes 140 autosomal entries, four X tivity on 4q31 and 9q31 (176). chromosome assignments and 16 mitochondrial DNA

896 Official Journal of the American College of Sports Medicine http://www.acsm-msse.org markers. There are 33 nuclear and one mitochondrial diabetes, cardiovascular disease, and other chronic dis- genome markers more than in 2003. Given the complex- eases associated with physical inactivity, an increased ity of the performance and health-related fitness pheno- understanding of how the genetic susceptibilities that types, it should be obvious that we have a long way to go lead to these diseases may interact with exercise and before we have a satisfactory understanding of the role of physical activity interventions is urgently needed. genetic inheritance on exercise related traits and in the Despite the fact that progress has not been as spectacular adaptation to a physically active lifestyle. A new section as in other areas, particularly common chronic diseases, added to the review this year is that of the role of genes there are a growing number of genes with at least a mini- and specific DNA sequence variations on the level of mum of evidence supporting their involvement in fitness sedentarism or the level of physical activity. Hopefully, it and performance related phenotypes. This is illustrated by will be of interest to all those who study the circum- the trends in the number of loci from 2000 to 2004 for the stances under which people change from a sedentary families of phenotypes as defined in this review. Table 16 behavior to a physically active lifestyle. As in previous presents this synthesis for the 10 classes of phenotypes years, we conclude that advances in the genomics of considered here. In each case, the number of genes or fitness and performance are registered at a very modest markers appears to increase steadily since the topic was first pace. Given the growing prevalence in obesity, Type 2 reviewed in 2000.

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