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. 2009 Sep 7;587(Pt 23):5577–5584. doi: 10.1113/jphysiol.2009.179283

Genetic basis of inter-individual variability in the effects of exercise on the alleviation of lifestyle-related diseases

Masayuki Mori 1, Keiichi Higuchi 1, Akihiro Sakurai 2, Yasuharu Tabara 3, Tetsuro Miki 4, Hiroshi Nose 5,6; Shinshu University Genetic Research Consortium
PMCID: PMC2805370  PMID: 19736300

Abstract

Habitual exercise training, including a high-intensity interval walking programme, improves cardiorespiratory fitness and alleviates lifestyle-related diseases, such as obesity, hypertension and dyslipidaemia. However, the extent of improvement has been shown to differ substantially among individuals for various exercise regimens. A body of literature has demonstrated that gene polymorphisms could account for the inter-individual variability in the improvement of risk factors for lifestyle-related diseases following exercise training. However, the fractions of the variability explained by the polymorphisms are small (∼5%). Also, it is likely that the effects of gene polymorphisms differ with exercise regimens and subject characteristics. These observations suggest the necessity for further studies to exhaustively identify such gene polymorphisms. More importantly, the physiological and molecular genetic mechanisms by which gene polymorphisms interact with exercise to influence the improvements of risk factors for lifestyle-related diseases differentially remain to be clarified. A better understanding of these issues should lead to more effective integration of exercise to optimize the treatment and management of individuals with lifestyle-related diseases.

Lifestyle-related diseases, which include obesity, diabetes, dyslipidaemia, hypertension and cardiovascular disease, represent the greatest global health threat. Epidemiological and clinical evidence indicates that poor cardiorespiratory fitness is a major risk factor for lifestyle-related diseases (Sawada et al. 1993, 2003; Wei et al. 1999; Lakka et al. 2001). Thus, the excess energy intake and adoption of a sedentary lifestyle by modern people can result in a decline in cardiorespiratory fitness, leading to the epidemic emergence of lifestyle-related diseases. In addition, cardiorespiratory fitness generally deteriorates with advancing age. In this regard, middle-aged and older individuals constitute another high-risk group for lifestyle-related diseases. Conversely, increasing cardiorespiratory fitness can be an effective measure in the prevention and alleviation of lifestyle-related diseases. One commonly recommended approach for increasing cardiorespiratory fitness and for decreasing the risks of, or alleviating the symptoms of lifestyle-related diseases is habitual exercise training, a low-cost, non-pharmacological intervention that is available to the vast majority of people (Kraus et al. 2002; Pescatello et al. 2004; O’Gorman & Krook, 2008). However, it has also become evident that the extent of improvement with exercise training differs substantially among individuals, irrespective of whether it is a standardized or controlled exercise-training programme (Bouchard & Rankinen, 2001). To appreciate the effects of exercise on prevention and alleviation of lifestyle-related diseases fully, it is indispensable to clarify the basis of the inter-individual variability.

Predisposition to lifestyle-related diseases has a genetic basis. Gene polymorphisms influence inter-individual variability in the predisposition to obesity (Rankinen et al. 2006) and hypertension (Levy et al. 2009; Newton-Cheh et al. 2009). Likewise, the inter-individual variability in the effects of exercise on alleviation of lifestyle-related diseases may be influenced by gene polymorphisms. Indeed, previous studies have consistently demonstrated involvement of genetic polymorphisms in the improvement of disease-related phenotypes for various exercise regimens. A genetic association study for the effects found a small collection of genes that influence improvement of diseases following habitual exercise training (Table 1). However, more studies are required to explore this hypothesis and establish a definitive gene–exercise relationship. Here, we briefly review the current status of the study of genetic associations of the effects of exercise on lifestyle-related diseases, including data obtained from our own study, and discuss a future perspective.

Table 1.

Gene polymorphisms reported to be associated with inter-individual variability in responsiveness to exercise training

Gene name Gene symbol dbSNP ID Location of SNP Effect of SNP Phenotype Selected reference
Fat mass and obesity associated gene FTO rs9939609* intron 1 — BMI Andreasen et al. (2008)
Insulin induced gene 2 INSIG2 rs7566605 5′ upstream (−10) — Fat volume Orkunoglu-Suer et al. (2008)
Uncoupling protein 1 UCP1 rs1800592* 5′ upstream (−3826) — Body weight Kogure et al. (1998)
Uncoupling protein 3 UCP3 rs1800849* 5′ upstream (−36) — BMI Otabe et al. (2000)
Peroxisome proliferator-activated receptor α PPARA rs1800206 exon 5 L162V Fat volume Uthurralt et al. (2007)
Peroxisome proliferator-activated receptor δ PPARD rs2267668 intron 2 — Inline graphic Stefan et al. (2007)
Peroxisome proliferator-activated receptor γ PPARG rs1805192 exon 2 A12P Body weight Lindi et al. (2002); Ostergard et al. (2005)
Cytochrome P450, family 19, subfamily A, polypeptide 1 CYP19A1 (TTTA)n repeat polymorphism intron 4 — BMI, fat mass, % body fat Tworoger et al. (2004)
Catechol-Omethyltransferase COMT rs4680 exon 4 V158M % body fat Tworoger et al. (2004)
Lipoprotein lipase LPL rs328* exon 9 S474X BMI Garenc et al. (2001)
Adrenergic receptor β2 ADRB2 rs1042713* exon 1 R16G Body weight, BMI, % body fat Sakane et al. (1999); Garenc et al. (2003)
rs1042714* exon 1 Q27E % body fat Meirhaeghe et al. (1999); Corbalán et al. (2002); Phares et al. (2004)
Adrenergic receptor β3 ADRB3 rs4994* exon 1 R64W Body weight, % body fat Yoshida et al. (1995); Phares et al. (2004)
Guanine nucleotide-binding protein β3 GNB3 rs5443 exon 10 aberrant splicing Obesity, fat mass, % body fat Rankinen et al. (2002); Grove et al. (2007)
Ectonucleotide pyrophosphatase/ phosphodiesterase ENPP1 rs1805101 exon 4 K171Q BMI Park et al. (2008)
Angiotensin I-converting enzyme ACE I/D polymorphism* intron 16 — Diastolic blood pressure, fat mass Hagberg et al. (1999); Montgomery et al. (1999)
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*

Polymorphisms examined in our study.

dbSNP ID: reference single nucleotide polymorphism identifier in SNPs database of NCBI (http://www.ncbi.nlm.nih.gov/SNP)

SNP: single nucleotide polymorphism

BMI: body mass index

VO2peak: peak aerobic capacity

Gene polymorphisms underlie the inter-individual variability in alleviation of lifestyle-related diseases following exercise training

There is a body of literature demonstrating associations between gene polymorphisms and exercise-training responsiveness of risk factors for lifestyle-related diseases (Table 1). Candidate genes come from a variety of functional categories. Several gene polymorphisms were reported to be associated with responsiveness of several risk factors. Angiotensin I-converting enzyme (ACE) is a dipeptidyl carboxypeptidase that plays an important role in blood pressure regulation and electrolyte balance. A polymorphism of the human ACE gene was identified in which the deletion rather than the insertion of a 287 bp fragment in intron 16 of the gene is associated with high tissue ACE activity (Danser et al. 1995). This insertion/deletion polymorphism influences not only the cardiovascular response (Hagberg et al. 1999), but also changes in body composition following exercise training (Montgomery et al. 1999). However, some gene–exercise interaction effects failed to be replicated in other studies. These facts imply a complex interrelationship among gene polymorphisms, exercise and lifestyle-related diseases. For more information, the interested reader can also refer to an excellent recent review on this topic (Bray et al. 2009).

Effects of high-intensity interval walking training are also dependent on gene polymorphisms

‘High-intensity interval walking’ is an aerobic exercise that improves cardiorespiratory fitness and alleviates lifestyle-related diseases in middle-aged and older individuals (Nemoto et al. 2007). We investigated the effects of a high-intensity interval walking training intervention in middle-aged and older Japanese females. Average initial values of this population (n = 217; 41–86 years of age; mean age, 63.3 years) for peak aerobic capacity Inline graphic, body mass index (BMI) and systolic blood pressure (SBP) were 20.5 ml kg−1 min−1, 23.7 kg m−2 and 133.3 mmHg, respectively. After 10 months of high-intensity interval walking training, the parameters improved significantly to 25.6 ml kg−1 min−1Inline graphic, 23.0 kg m−2 (BMI) and 130.3 mmHg (SBP). Among the 217 subjects, 57 had an initial BMI ≥ 25 kg m−2, which is the threshold value for the clinical diagnosis of obesity in Japan. Eighty-two had an initial SBP ≥ 140 mmHg, which is the threshold value for the clinical diagnosis of hypertension in Japan. Importantly, improvement was prominent for these subjects. In the obese subjects, BMI decreased significantly from 27.6 to 26.4 kg m−2. In the hypertensive subjects, SBP decreased significantly from 148.3 to 140.9 mmHg. However, the change scores in these parameters differed substantially among individuals (Fig. 1).

Figure 1. Distribution of change score inInline graphic(n= 217), body mass index in obese subjects (BMI ≥ 25 kg m−2; n= 57) and systolic blood pressure in hypertensive subjects (SBP ≥ 140 mmHg; n= 82) after 10 months of high-intensity interval walking exercise training.

Figure 1

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Grey bars represent subjects with improvement, whereas open bars represent subjects with no change or aggravation.

Next, a study was performed to determine the association between the change score and gene polymorphisms. Most of these polymorphisms were reported to be associated with inter-individual variability in the effects of exercise on the improvement of obesity or hypertension (Table 1). Our results, however, failed to replicate the gene–exercise interaction effects or pre- and post-training values for most polymorphisms. This discrepancy may be partly explained by differences in the exercise regimen, such as type (e.g. aerobic or endurance), strength, frequency and duration. The gene–exercise interaction would also be influenced by subject characteristics, such as ethnicity, age, sex, energy intake and baseline physical activity. A single nucleotide polymorphism (SNP), rs1042713, in the adrenergic receptor β2 (ADRB2) gene (also known as a Gly16Arg polymorphism) was found to be associated with the change score in BMI in obese subjects (Fig. 2). The Arg allele was associated with a greater reduction of BMI following exercise training. This polymorphism explained 12.5% of the inter-individual variability in change scores following exercise training. This result was consistent with one of the previous reports (Garenc et al. 2003), but inconsistent with the other report (Sakane et al. 1999), in which the Gly allele was associated with a greater reduction in body weight, implying intricate gene–exercise interaction.

Figure 2. Association of a SNP rs1042713 in the ADRB2 genes and change in BMI in obese subjects (BMI ≥ 25 kg m−2; n = 57) after 10 months of high-intensity interval walking training.

Figure 2

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Stepwise multiple regression analysis was employed. This figure shows the result drawn by a simple linear regression analysis. Average initial values for BMI and energy expenditure from high-intensity walking were not statistically different between genotypes. The change score in BMI was not correlated with age or initial BMI value.

Towards comprehensive identification of polymorphisms for effects of exercise training

In order to attain full comprehension of intricate gene–exercise interaction in alleviation of lifestyle-related diseases, two major subjects need to be achieved in the future. Firstly, it is necessary to exhaustively identify candidate gene polymorphisms associated with alleviation of lifestyle-related diseases following exercise training. So far, most of the studies have employed a candidate gene approach, in which only one or a few specific genes of interest were examined. The choice of candidate polymorphisms has primarily been based on the hypothesis that the polymorphisms, which determine the predisposition to lifestyle-related diseases, would also be a determinant of recovery feasibility from the diseases following exercise. This hypothesis was true for several genes, such as ACE (Rush & Aultman, 2008) and fat mass and obesity associated gene (FTO) (Frayling et al. 2007). However, it might not always be the case. Furthermore, the sample sizes in previous studies were generally too small (∼1000) to provide adequate statistical power. Currently, a genome-wide association study, which allows simultaneous examination of over 50 000 polymorphisms without accompanying hypothesis in thousands of subjects, is becoming the main strategy to analyse the genetic basis of predisposition to lifestyle-related diseases (The Wellcome Trust Genome Case Control Consortium, 2007). This approach confirmed the results obtained by the candidate gene approach with more strict statistical conditions. More importantly, it resulted in successful discoveries of hundreds of new SNPs for lifestyle-related diseases (Thorleifsson et al. 2008; Willer et al. 2009; Levy et al. 2009; Newton-Cheh et al. 2009), implying the greatest promise also for comprehensive identification of polymorphisms for even more intricate gene–exercise interaction in alleviation of the diseases.

Towards elucidation of the mechanisms for the genotype-dependent effects of exercise training

Secondly, the physiological and molecular genetic mechanisms by which the variations in the genes exert genotype-dependent differential effects on alleviation of lifestyle-related diseases following exercise training remain to be clarified. Habitual exercise training induces multiple adaptations within skeletal muscle. Also, exercise training elicits improvements in endothelium-dependent dilatation or reduces sympathetic activity. Thus, exercise training is considered to elicit metabolic as well as physiological reprogramming systemically, which contributes to alleviation of lifestyle-related diseases. Alterations in actions of plenty of genes through epigenetic modification, changes in expression level and stability of transcripts, post-translational modification of gene products and other mechanisms undoubtedly underlie this reprogramming process. Common gene polymorphisms may have only a negligible or subtle influence on gene functions in sedentary conditions. Exercise training may amplify the differential effects between polymorphic alleles, which then manifest as differences in responsiveness to exercise between individuals (Fig. 3). Indeed, a few studies have demonstrated that nucleotide polymorphisms caused differences in gene expression level after exercise training (Prior et al. 2006; Oberbach et al. 2008). This, in addition to other possibilities, should be studied in the future. This would be achieved by integration of data obtained from two different approaches. Firstly, responses of each candidate polymorphic gene to exercise training should be carefully examined at various levels from DNA to a mature protein product. A second useful approach is transcriptome, proteome and physiome analysis, which would give a comprehensive picture of physiological dynamics occurring after exercise training.

Figure 3.

Figure 3

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Proposed model of allele–exercise interaction for alleviation of lifestyle-related diseases

Conclusion

It is evident that gene polymorphisms play a crucial role in determination of the improvement of risk factors for lifestyle-related diseases following exercise training. Full comprehension of gene polymorphism–exercise interaction in alleviation of the diseases should help in the development of individualized training programmes to optimize the treatment and management of subjects with lifestyle-related diseases. It should also provide clues as to which pathways to target with agents that mimic or potentiate the effects of exercise for the treatment of lifestyle-related diseases (Narkar et al. 2008; Hawley & Holloszy, 2009).

Acknowledgments

This work was supported in part by the Shinshu University Partnership Project between Shinshu University, Jukunen Taiiku Daigaku Research Center (JTRC), the Ministry of Education, Culture, Sports, Science and Technology of Japan, Matsumoto City, Sanyo Electric Co., Japan. This work was also supported also by a Grant-in-Aid for Scientific Research from the Ministry of Health, Labor and Welfare of Japan.

Glossary

Abbreviations

ACE

angiotensin I-converting enzyme

ADRB2

adrenergic receptor β2

BMI

body mass index

FTO

, fat mass and obesity associated gene

SBP

systolic blood pressure

Inline graphic, peak aerobic capacity.

Author contributions

All authors contributed to the conception and design of the study, interpretation of data and drafting and revising the manuscript. M.M. performed experiments and analysed the data. K.H. performed experiments. A.S. analysed the data. Y.T. performed experiments. T.M. performed experiments. H.N. performed experiments. All authors approved the published version of the manuscript. All the experiments were done at the Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine.

Author addresses

Shinshu University Genetic Research Consortium: Hiroshi Nose1, Shizue Masuki1, Keiichi Higuchi2, Masayuki Mori2, Jinko Sawashita2, Shun’ichiro Taniguchi3, Michiko Takeoka3, Koki Nakajima3, Yoshimitsu Fukushima4, Akihiro Sakurai4, Shin-ichi Usami5, Shigenari Hashimoto5,6 and Kenji Sano7: 1Department of Sports Medical Sciences, Institute on Aging and Adaptation, 2Department of Aging Biology, Institute on Aging and Adaptation, 3Department of Molecular Oncology, Institute on Aging and Adaptation, 4Department of Medical Genetics, 5Department of Otorhinolaryngology, 6Preventive Medical Center and 7Department of Laboratory Medicine.

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