Interaction Between Exercise and Genetics in Type 2 Diabetes Mellitus: An Epidemiological Perspective

  • Paul W. FranksEmail author
  • Ema C. Brito
Part of the Molecular and Translational Medicine book series (MOLEMED)


Type 2 diabetes mellitus is a heterogeneous disease characterized by an inability to transport glucose from the blood into the cells. The disease has genetic and lifestyle determinants and probably results from the interaction of these risk factors. While this notion is widely accepted and endorsed, the available evidence is far from concrete. In this chapter the evidence that implicates physical inactivity and common genetic variation in type 2 diabetes risk will be described. Then, the fundamental concepts of gene × exercise interactions in type 2 diabetes will be defined by summarizing the evidence from epidemiological studies and clinical trials that have tested related hypotheses. The penultimate section of this chapter discusses the strengths and limitations of existing studies of interaction and outlines some of the common methodological hurdles inherent when testing hypotheses of gene × exercise interactions. The chapter concludes with a short section looking forward to where this field of research is heading and the possibilities for clinical translation.


Type 2 diabetes Genetics Genotype Interaction Effect-modification Epidemiology Clinical trials Exercise Physical activity 


  1. 1.
    Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047–53.PubMedCrossRefGoogle Scholar
  2. 2.
    Hu FB, Manson JE, Stampfer MJ, Colditz G, Liu S, Solomon CG, et al. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl J Med. 2001;345(11):790–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Hu FB, Li TY, Colditz GA, Willett WC, Manson JE. Television watching and other sedentary behaviors in relation to risk of obesity and type 2 diabetes mellitus in women. JAMA. 2003;289(14):1785–91.PubMedCrossRefGoogle Scholar
  4. 4.
    Dunstan DW, Salmon J, Healy GN, Shaw JE, Jolley D, Zimmet PZ, et al. Association of television viewing with fasting and 2-h postchallenge plasma glucose levels in adults without diagnosed diabetes. Diabetes Care. 2007;30(3):516–22.PubMedCrossRefGoogle Scholar
  5. 5.
    Davis N, Forbes B, Wylie-Rosett J. Nutritional strategies in type 2 diabetes mellitus. Mt Sinai J Med. 2009;76(3):257–68.PubMedCrossRefGoogle Scholar
  6. 6.
    Hu FB, van Dam RM, Liu S. Diet and risk of Type II diabetes: the role of types of fat and carbohydrate. Diabetologia. 2001;44(7):805–17.PubMedCrossRefGoogle Scholar
  7. 7.
    Winzell MS, Ahren B. The high-fat diet-fed mouse: a model for studying mechanisms and treatment of impaired glucose tolerance and type 2 diabetes. Diabetes. 2004;53 Suppl 3:S215–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403.PubMedCrossRefGoogle Scholar
  9. 9.
    Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344(18):1343–50.PubMedCrossRefGoogle Scholar
  10. 10.
    Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, et al. Nat Genet. 2010; 42(7):579–89.PubMedCrossRefGoogle Scholar
  11. 11.
    Maher B. Personal genomes: the case of the missing heritability. Nature. 2008;456(7218): 18–21.PubMedCrossRefGoogle Scholar
  12. 12.
    Physical activity and health: A Report of the Surgeon General (1996). U.S. Deparment of Health and Human Services, Atlanta, GA.Google Scholar
  13. 13.
    American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2009;32 Suppl 1:S62–7.CrossRefGoogle Scholar
  14. 14.
    Lillioja S, Mott DM, Spraul M, Ferraro R, Foley JE, Ravussin E, et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med. 1993;329(27):1988–92.PubMedCrossRefGoogle Scholar
  15. 15.
    Festa A, Williams K, D’Agostino Jr R, Wagenknecht LE, Haffner SM. The natural course of beta-cell function in nondiabetic and diabetic individuals: the Insulin Resistance Atherosclerosis Study. Diabetes. 2006;55(4):1114–20.PubMedCrossRefGoogle Scholar
  16. 16.
    Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003;26 Suppl 1:S5–20.Google Scholar
  17. 17.
    The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 1997;20(7):1183–97.Google Scholar
  18. 18.
    Forouhi NG, Balkau B, Borch-Johnsen K, Dekker J, Glumer C, Qiao Q, et al. The threshold for diagnosing impaired fasting glucose: a position statement by the European Diabetes Epidemiology Group. Diabetologia. 2006;49(5):822–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Genuth S, Alberti KG, Bennett P, Buse J, Defronzo R, Kahn R, et al. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care. 2003;26(11):3160–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Unwin N, Shaw J, Zimmet P, Alberti KG. Impaired glucose tolerance and impaired fasting glycaemia: the current status on definition and intervention. Diabet Med. 2002;19(9):708–23.PubMedCrossRefGoogle Scholar
  21. 21.
    Saydah SH, Loria CM, Eberhardt MS, Brancati FL. Subclinical states of glucose intolerance and risk of death in the U.S. Diabetes Care. 2001;24(3):447–53.PubMedCrossRefGoogle Scholar
  22. 22.
    American Diabetes Association. Screening for type 2 diabetes. Diabetes Care. 2004;27 Suppl 1:S11–4.Google Scholar
  23. 23.
    Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, et al. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet. 2008;40(5):638–45.PubMedCrossRefGoogle Scholar
  24. 24.
    Lyssenko V, Jonsson A, Almgren P, Pulizzi N, Isomaa B, Tuomi T, et al. Clinical risk factors, DNA variants, and the development of type 2 diabetes. N Engl J Med. 2008;359(21):2220–32.PubMedCrossRefGoogle Scholar
  25. 25.
    Lyssenko V, Almgren P, Anevski D, Orho-Melander M, Sjogren M, Saloranta C, et al. Genetic prediction of future type 2 diabetes. PLoS Med. 2005;2(12):e345.PubMedCrossRefGoogle Scholar
  26. 26.
    Franks PW, Mesa JL, Harding AH, Wareham NJ. Gene-lifestyle interaction on risk of type 2 diabetes. Nutr Metab Cardiovasc Dis. 2007;17(2):104–24.PubMedCrossRefGoogle Scholar
  27. 27.
    Zimmet PZ. Diabetes epidemiology as a tool to trigger diabetes research and care. Diabetologia. 1999;42(5):499–518.PubMedCrossRefGoogle Scholar
  28. 28.
    Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339(4):229–34.PubMedCrossRefGoogle Scholar
  29. 29.
    Fox CS, Coady S, Sorlie PD, D’Agostino RB, Pencina MJ, Vasan RS, et al. Increasing cardiovascular disease burden due to diabetes mellitus: the Framingham Heart Study. Circulation. 2007;115(12):1544–50.PubMedCrossRefGoogle Scholar
  30. 30.
    Jansson SP, Andersson DK, Svardsudd K. Prevalence and incidence rate of diabetes mellitus in a Swedish community during 30 years of follow-up. Diabetologia. 2007;50(4):703–10.PubMedCrossRefGoogle Scholar
  31. 31.
    Eliasson M, Lindahl B, Lundberg V, Stegmayr B. No increase in the prevalence of known diabetes between 1986 and 1999 in subjects 25-64 years of age in northern Sweden. Diabet Med. 2002;19(10):874–80.PubMedCrossRefGoogle Scholar
  32. 32.
    Berger B, Stenstrom G, Chang YF, Sundkvist G. The prevalence of diabetes in a Swedish population of 280,411 inhabitants. A report from the Skaraborg Diabetes Registry. Diabetes Care. 1998;21(4):546–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Jonsson B. Revealing the cost of Type II diabetes in Europe. Diabetologia. 2002;45(7):S5–12.PubMedCrossRefGoogle Scholar
  34. 34.
    Franks PW, Looker HC, Kobes S, Touger L, Tataranni PA, Hanson RL, et al. Gestational glucose tolerance and risk of type 2 ­diabetes in young Pima Indian offspring. Diabetes. 2006;55(2):460–5.PubMedCrossRefGoogle Scholar
  35. 35.
    Wiegand S, Maikowski U, Blankenstein O, Biebermann H, Tarnow P, Gruters A. Type 2 diabetes and impaired glucose tolerance in European children and adolescents with obesity – a problem that is no longer restricted to minority groups. Eur J Endocrinol. 2004;151(2):199–206.PubMedCrossRefGoogle Scholar
  36. 36.
    Singh R, Shaw J, Zimmet P. Epidemiology of childhood type 2 diabetes in the developing world. Pediatr Diabetes. 2004;5(3):154–68.PubMedCrossRefGoogle Scholar
  37. 37.
    Ortega-Rodriguez E, Levy-Marchal C, Tubiana N, Czernichow P, Polak M. Emergence of type 2 diabetes in an hospital based cohort of children with diabetes mellitus. Diabetes Metab. 2001;27(5 Pt 1):574–8.PubMedGoogle Scholar
  38. 38.
    Rami B, Schober E, Nachbauer E, Waldhor T. Type 2 diabetes mellitus is rare but not absent in children under 15 years of age in Austria. Eur J Pediatr. 2003;162(12):850–2.PubMedCrossRefGoogle Scholar
  39. 39.
    Haines L, Wan KC, Lynn R, Barrett TG, Shield JP. Rising incidence of type 2 diabetes in children in the U.K. Diabetes Care. 2007;30(5):1097–101.PubMedCrossRefGoogle Scholar
  40. 40.
    DECODE Study Group. Age- and sex-specific prevalences of diabetes and impaired glucose regulation in 13 European cohorts. Diabetes Care. 2003;26(1):61–9.CrossRefGoogle Scholar
  41. 41.
    Hussain A, Claussen B, Ramachandran A, Williams R. Prevention of type 2 diabetes: a review. Diabetes Res Clin Pract. 2007;76(3):317–26.PubMedCrossRefGoogle Scholar
  42. 42.
    Colagiuri S, Borch-Johnsen K, Glumer C, Vistisen D. There really is an epidemic of type 2 diabetes. Diabetologia. 2005;48(8):1459–63.PubMedCrossRefGoogle Scholar
  43. 43.
    Saltin B, Lindgarde F, Houston M, Horlin R, Nygaard E, Gad P. Physical training and glucose tolerance in middle-aged men with chemical diabetes. Diabetes. 1979;28 Suppl 1:30–2.PubMedGoogle Scholar
  44. 44.
    Holloszy JO, Schultz J, Kusnierkiewicz J, Hagberg JM, Ehsani AA. Effects of exercise on glucose tolerance and insulin resistance. Brief review and some preliminary results. Acta Med Scand Suppl. 1986;711:55–65.PubMedGoogle Scholar
  45. 45.
    Zierath JR, Wallberg-Henriksson H. Exercise training in obese diabetic patients. Special considerations. Sports Med. 1992;14(3):171–89.PubMedCrossRefGoogle Scholar
  46. 46.
    Carnethon MR, Craft LL. Autonomic regulation of the association between exercise and diabetes. Exerc Sport Sci Rev. 2008;36(1):12–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Boule NG, Haddad E, Kenny GP, Wells GA, Sigal RJ. Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials. JAMA. 2001;286(10):1218–27.PubMedCrossRefGoogle Scholar
  48. 48.
    Eriksson KF, Lindgarde F. Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise. The 6-year Malmo feasibility study. Diabetologia. 1991;34(12):891–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care. 1997;20(4):537–44.PubMedCrossRefGoogle Scholar
  50. 50.
    Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V. The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia. 2006;49(2):289–97.PubMedCrossRefGoogle Scholar
  51. 51.
    Bouchard C, Leon AS, Rao DC, Skinner JS, Wilmore JH, Gagnon J. The HERITAGE family study. Aims, design, and measurement protocol. Med Sci Sports Exerc. 1995;27(5):721–9.PubMedGoogle Scholar
  52. 52.
    Helmrich SP, Ragland DR, Leung RW, Paffenbarger Jr RS. Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med. 1991;325(3):147–52.PubMedCrossRefGoogle Scholar
  53. 53.
    Manson JE, Rimm EB, Stampfer MJ, Colditz GA, Willet WC, Krolewski AS, et al. Physical activity and incidence of non-insulin-dependent diabetes mellitus in women. Lancet. 1991;338(8770):774–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Hu FB, Sigal RJ, Rich-Edwards JW, Golditz GA, Solomon CG, Willet WC, et al. Walking compared with vigorous physical activity and risk of type 2 diabetes in women: a prospective study. JAMA. 1999;282(15):1433–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Hu FB, Leitzmann MF, Stampfer MJ, Colditz GA, Willett WC, Rimm EB. Physical activity and television watching in relation to risk for type 2 diabetes mellitus in men. Arch Intern Med. 2001;161(12):1542–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Visscher PM, Hill WG, Wray NR. Heritability in the genomics era – concepts and misconceptions. Nat Rev Genet. 2008;9(4):255–66.PubMedCrossRefGoogle Scholar
  57. 57.
    Kaprio J, Tuomilehto J, Koskenvuo M, Romanov K, Reunanen A, Eriksson J, et al. Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia. 1992;35(11):1060–7.PubMedCrossRefGoogle Scholar
  58. 58.
    Poulsen P, Kyvik KO, Vaag A, Beck-Nielsen H. Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance – a population-based twin study. Diabetologia. 1999;42(2):139–45.PubMedCrossRefGoogle Scholar
  59. 59.
    Barroso I. Genetics of Type 2 diabetes. Diabet Med. 2005;22(5):517–35.PubMedCrossRefGoogle Scholar
  60. 60.
    Meigs JB, Cupples LA, Wilson PW. Parental transmission of type 2 diabetes: the Framingham Offspring Study. Diabetes. 2000;49(12):2201–7.PubMedCrossRefGoogle Scholar
  61. 61.
    Gottlieb MS, Root HF. Diabetes mellitus in twins. Diabetes. 1968;17(11):693–704.PubMedGoogle Scholar
  62. 62.
    Barnett AH, Eff C, Leslie RD, Pyke DA. Diabetes in identical twins. A study of 200 pairs. Diabetologia. 1981;20(2):87–93.PubMedCrossRefGoogle Scholar
  63. 63.
    Newman B, Selby JV, King MC, Slemenda C, Fabsitz R, Friedman GD. Concordance for type 2 (non-insulin-dependent) diabetes mellitus in male twins. Diabetologia. 1987;30(10):763–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Medici F, Hawa M, Ianari A, Pyke DA, Leslie RD. Concordance rate for type II diabetes mellitus in monozygotic twins: actuarial analysis. Diabetologia. 1999;42(2):146–50.PubMedCrossRefGoogle Scholar
  65. 65.
    Elbein SC, Hasstedt SJ, Wegner K, Kahn SE. Heritability of pancreatic beta-cell function among nondiabetic members of Caucasian familial type 2 diabetic kindreds. J Clin Endocrinol Metab. 1999;84(4):1398–403.PubMedCrossRefGoogle Scholar
  66. 66.
    Elbein SC, Wegner K, Kahn SE. Reduced beta-cell compensation to the insulin resistance associated with obesity in members of Caucasian familial type 2 diabetic kindreds. Diabetes Care. 2000;23(2):221–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Gerich JE. The genetic basis of type 2 diabetes mellitus: impaired insulin secretion versus impaired insulin sensitivity. Endocr Rev. 1998;19(4):491–503.PubMedCrossRefGoogle Scholar
  68. 68.
    Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, et al. The sequence of the human genome. Science. 2001;291(5507):1304–51.PubMedCrossRefGoogle Scholar
  69. 69.
    Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409(6822):860–921.PubMedCrossRefGoogle Scholar
  70. 70.
    International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature. 2004;431(7011):931–45.CrossRefGoogle Scholar
  71. 71.
    Kruglyak L, Nickerson DA. Variation is the spice of life. Nat Genet. 2001;27(3):234–6.PubMedCrossRefGoogle Scholar
  72. 72.
    Hardy J, Singleton A. Genomewide association studies and human disease. N Engl J Med. 2009;360(17):1759–68.PubMedCrossRefGoogle Scholar
  73. 73.
    Grarup N, Rose CS, Andersson EA, Andessen G, Nielsen AL, Albrechtsen A,et al. Studies of association of variants near the HHEX, CDKN2A/B, and IGF2BP2 genes with type 2 diabetes and impaired insulin release in 10, 705 Danish subjects: validation and extension of genome-wide association studies. Diabetes. 2007;56(12):3105–11.PubMedCrossRefGoogle Scholar
  74. 74.
    Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliot KS, Lango H, et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science. 2007;316(5829):1336–41.PubMedCrossRefGoogle Scholar
  75. 75.
    Steinthorsdottir V, Thorleifsson G, Reynisdottir I, Benediktsson R, Jonsdottir T, Walters GB, et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet. 2007;39(6):770–5.PubMedCrossRefGoogle Scholar
  76. 76.
    Sladek R, Rocheleau G, Rung J, Rocheleau G, Rung J, Dina C, et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature. 2007;445(7130):881–5.PubMedCrossRefGoogle Scholar
  77. 77.
    Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PIW, Chen H, et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007;316(5829):1331–6.PubMedCrossRefGoogle Scholar
  78. 78.
    Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007;316(5829):1341–5.PubMedCrossRefGoogle Scholar
  79. 79.
    Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet. 2010;42(7):579–89.PubMedCrossRefGoogle Scholar
  80. 80.
    Prokopenko I, McCarthy MI, Lindgren CM. Type 2 diabetes: new genes, new understanding. Trends Genet. 2008;24(12):613–21.PubMedCrossRefGoogle Scholar
  81. 81.
    Florez JC. Newly identified loci highlight beta cell dysfunction as a key cause of type 2 diabetes: where are the insulin resistance genes? Diabetologia. 2008;51(7):1100–10.PubMedCrossRefGoogle Scholar
  82. 82.
    Ottman R. Gene-environment interaction: definitions and study designs. Prev Med. 1996;25(6):764–70.PubMedCrossRefGoogle Scholar
  83. 83.
    Rothman KJ, Greenland S, Walker AM. Concepts of interaction. Am J Epidemiol. 1980;112(4):467–70.PubMedGoogle Scholar
  84. 84.
    Yang Q, Khoury MJ. Evolving methods in genetic epidemiology. III. Gene-environment interaction in epidemiologic research. Epidemiol Rev. 1997;19(1):33–43.PubMedGoogle Scholar
  85. 85.
    Semenza JC, Ziogas A, Largent J, Peel D, Anton-Culver H. Gene-environment interactions in renal cell carcinoma. Am J Epidemiol. 2001;153(9):851–9.PubMedCrossRefGoogle Scholar
  86. 86.
    Mucci LA, Wedren S, Tamimi RM, Trichopoulos D, Adami HO. The role of gene-environment interaction in the aetiology of human cancer: examples from cancers of the large bowel, lung and breast. J Intern Med. 2001;249(6):477–93.PubMedCrossRefGoogle Scholar
  87. 87.
    Lake SL, Laird NM. Tests of gene-environment interaction for case-parent triads with general environmental exposures. Ann Hum Genet. 2004;68(Pt 1):55–64.PubMedCrossRefGoogle Scholar
  88. 88.
    Umbach DM, Weinberg CR. The use of case-parent triads to study joint effects of genotype and exposure. Am J Hum Genet. 2000;66(1):251–61.PubMedCrossRefGoogle Scholar
  89. 89.
    Khoury MJ, Flanders WD. Nontraditional epidemiologic approaches in the analysis of gene-environment interaction: case-control studies with no controls! Am J Epidemiol. 1996;144(3):207–13.PubMedGoogle Scholar
  90. 90.
    Kraft P, Yen YC, Stram DO, Morrison J, Gauderman WJ. Exploiting gene-environment interaction to detect genetic associations. Hum Hered. 2007;63(2):111–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Franks PW. Identifying genes for primary hypertension: methodological limitations and gene-environment interactions. J Hum Hypertens. 2009;23(4):227–37.PubMedCrossRefGoogle Scholar
  92. 92.
    Clayton D, McKeigue PM. Epidemiological methods for studying genes and environmental factors in complex diseases. Lancet. 2001;358(9290):1356–60.PubMedCrossRefGoogle Scholar
  93. 93.
    Meirhaeghe A, Helbecque N, Cottel D, Amouyel P. Beta2-adrenoceptor gene polymorphism, body weight, and physical activity. Lancet. 1999;353(9156):896.PubMedCrossRefGoogle Scholar
  94. 94.
    Meirhaeghe A, Luan J, Franks PW, Hennings S, Mitchell J, Halsall D, et al. The effect of the Gly16Arg polymorphism of the beta(2)-adrenergic receptor gene on plasma free fatty acid levels is modulated by physical activity. J Clin Endocrinol Metab. 2001;86(12):5881–7.PubMedCrossRefGoogle Scholar
  95. 95.
    Corbalan MS, Marti A, Forga L, Martinez-Gonzalez MA, Martinez JA. The 27Glu polymorphism of the beta2-adrenergic receptor gene interacts with physical activity influencing obesity risk among female subjects. Clin Genet. 2002;61(4):305–7.PubMedCrossRefGoogle Scholar
  96. 96.
    Nemoto M, Sasaki T, Deeb SS, Fujimoto WY, Tajima N. Differential effect of PPARgamma2 variants in the development of type 2 diabetes between native Japanese and Japanese Americans. Diabetes Res Clin Pract. 2002;57(2):131–7.PubMedCrossRefGoogle Scholar
  97. 97.
    Luan J, Browne PO, Harding AH, Halsall DJ, O’Rahilly S, Chatterjee VKK, et al. Evidence for gene-nutrient interaction at the PPARgamma locus. Diabetes. 2001;50(3):686–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Memisoglu A, Hu FB, Hankinson SE, Manson JE, De Vivo I, Willet WC, et al. Interaction between a peroxisome proliferator-activated receptor gamma gene polymorphism and dietary fat intake in relation to body mass. Hum Mol Genet. 2003;12(22):2923–9.PubMedCrossRefGoogle Scholar
  99. 99.
    Robitaille J, Despres JP, Perusse L, Vohl MC. The PPAR-gamma P12A polymorphism modulates the relationship between dietary fat intake and components of the metabolic syndrome: results from the Quebec Family Study. Clin Genet. 2003;63(2):109–16.PubMedCrossRefGoogle Scholar
  100. 100.
    Pisabarro RE, Sanguinetti C, Stoll M, Prendez D. High incidence of type 2 diabetes in peroxisome proliferator-activated receptor gamma2 Pro12Ala carriers exposed to a high chronic intake of trans fatty acids and saturated fatty acids. Diabetes Care. 2004;27(9):2251–2.PubMedCrossRefGoogle Scholar
  101. 101.
    Franks PW, Luan J, Browne PO, Harding AH, O’Rahilly S, Chatterjee VKK, et al. Does peroxisome proliferator-activated receptor gamma genotype (Pro12ala) modify the association of physical activity and dietary fat with fasting insulin level? Metabolism. 2004;53(1):11–6.PubMedCrossRefGoogle Scholar
  102. 102.
    Nelson TL, Fingerlin TE, Moss LK, Barmada MM, Ferrell RE, Norris JM. Association of the peroxisome proliferator-activated receptor gamma gene with type 2 diabetes mellitus varies by physical activity among non-Hispanic whites from Colorado. Metabolism. 2007;56(3):388–93.PubMedCrossRefGoogle Scholar
  103. 103.
    Otabe S, Clement K, Rich N, Warden C, Pecqueur C, Neverova M, et al. Mutation screening of the human UCP 2 gene in normoglycemic and NIDDM morbidly obese patients: lack of association between new UCP 2 polymorphisms and obesity in French Caucasians. Diabetes. 1998;47(5):840–2.PubMedCrossRefGoogle Scholar
  104. 104.
    Berentzen T, Dalgaard LT, Petersen L, Pedersen O, Sorensen TI. Interactions between physical activity and variants of the genes encoding uncoupling proteins -2 and -3 in relation to body weight changes during a 10-y follow-up. Int J Obes (Lond). 2005;29(1):93–9.CrossRefGoogle Scholar
  105. 105.
    Grarup N, Andreasen CH, Andersen MK, Albrechtsen A, Sandbaek A, Lauritzen T, et al. The -250G>A promoter variant in hepatic lipase associates with elevated fasting serum high-density lipoprotein cholesterol modulated by interaction with physical activity in a study of 16, 156 Danish subjects. J Clin Endocrinol Metab. 2008;93(6):2294–9.PubMedCrossRefGoogle Scholar
  106. 106.
    Hokanson JE, Kamboh MI, Scarboro S, Eckel RH, Hamman RF. Effects of the hepatic lipase gene and physical activity on coronary heart disease risk. Am J Epidemiol. 2003;158(9):836–43.PubMedCrossRefGoogle Scholar
  107. 107.
    Corella D, Guillen M, Saiz C, Portolés O, Sabater A, Cortina S, et al. Environmental factors modulate the effect of the APOE genetic polymorphism on plasma lipid concentrations: ecogenetic studies in a Mediterranean Spanish population. Metabolism. 2001;50(8):936–44.PubMedCrossRefGoogle Scholar
  108. 108.
    Bernstein MS, Costanza MC, James RW, Morris MA, Cambien F, Raoux S, et al. Physical activity may modulate effects of ApoE genotype on lipid profile. Arterioscler Thromb Vasc Biol. 2002;22(1):133–40.PubMedCrossRefGoogle Scholar
  109. 109.
    Boer JM, Kuivenhoven JA, Feskens EJ, Schouten EG, Havekes LM, Seidell JC, et al. Physical activity modulates the effect of a lipoprotein lipase mutation (D9N) on plasma lipids and lipoproteins. Clin Genet. 1999;56(2):158–63.PubMedCrossRefGoogle Scholar
  110. 110.
    Senti M, Elosua R, Tomas M, Sala J, Masiá R, Ordovás JM, et al. Physical activity modulates the combined effect of a common variant of the lipoprotein lipase gene and smoking on serum triglyceride levels and high-density lipoprotein cholesterol in men. Hum Genet. 2001;109(4):385–92.PubMedCrossRefGoogle Scholar
  111. 111.
    Grove ML, Morrison A, Folsom AR, Boerwinkle E, Hoelscher DM, Bray MS. Gene-environment interaction and the GNB3 gene in the atherosclerosis risk in communities study. Int J Obes (Lond). 2007;31(6):919–26.CrossRefGoogle Scholar
  112. 112.
    Franks PW, Luan J, Barroso I, Brage S, Gonzalez Sanchez JL, Ekelund U, et al. Variation in the eNOS gene modifies the association between total energy expenditure and glucose intolerance. Diabetes. 2005;54(9):2795–801.PubMedCrossRefGoogle Scholar
  113. 113.
    Kimura T, Yokoyama T, Matsumura Y, Yoshiike N, Date C, Muramatsu M, et al. NOS3 genotype-dependent correlation between blood pressure and physical activity. Hypertension. 2003;41(2):355–60.PubMedCrossRefGoogle Scholar
  114. 114.
    Vimaleswaran KS, Franks PW, Barroso I, Brage S, Ekelund U, Wareham NJ, et al. Habitual energy expenditure modifies the association between NOS3 gene polymorphisms and blood pressure. Am J Hypertens. 2008;21(3):297–302.PubMedCrossRefGoogle Scholar
  115. 115.
    Franks PW, Bhattacharyya S, Luan J, Montague C, Brennand J, Challis B, et al. Association between physical activity and blood pressure is modified by variants in the G-protein coupled receptor 10. Hypertension. 2004;43(2):224–8.PubMedCrossRefGoogle Scholar
  116. 116.
    Andreasen CH, Stender-Petersen KL, Mogensen MS, Torekov SS, Wegner L, Andersen G, et al. Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation. Diabetes. 2008;57(1):95–101.PubMedCrossRefGoogle Scholar
  117. 117.
    Rampersaud E, Mitchell BD, Pollin TI, Fu M, Shen H, O’Connell JR, et al. Physical activity and the association of common FTO gene variants with body mass index and obesity. Arch Intern Med. 2008;168(16):1791–7.PubMedCrossRefGoogle Scholar
  118. 118.
    Vimaleswaran KS, Li S, Zhao JH, Luan J, Bingham SA, Khaw T, et al. Physical activity attenuates the body mass index-increasing influence of genetic variation in the FTO gene. Am J Clin Nutr. 2009;90(2):425–8.PubMedCrossRefGoogle Scholar
  119. 119.
    Sonestedt E, Roos C, Gullberg B, Ericson U, Wirfalt E, Orho-Melander M. Fat and carbohydrate intake modify the association between genetic variation in the FTO genotype and obesity. Am J Clin Nutr. 2009;90(5):1418–25.PubMedCrossRefGoogle Scholar
  120. 120.
    Cauchi S, Stutzmann F, Cavalcanti-Proenca C, Durand E, Pouta A, Hartikainen, et al. Combined effects of MC4R and FTO common genetic variants on obesity in European general populations. J Mol Med. 2009;87(5):537–46.PubMedCrossRefGoogle Scholar
  121. 121.
    Herbert A, Gerry NP, McQueen MB, Heid IM, Pfeufer A, Illig T, et al. A common genetic variant is associated with adult and childhood obesity. Science. 2006;312(5771):279–83.PubMedCrossRefGoogle Scholar
  122. 122.
    Heid IM, Huth C, Loos RJ, Kronenberg F, Adamkova V, Anand SS, et al. Meta-analysis of the INSIG2 association with obesity including 74, 345 individuals: does heterogeneity of estimates relate to study design? PLoS Genet. 2009;5(10):e1000694.PubMedCrossRefGoogle Scholar
  123. 123.
    Andreasen CH, Mogensen MS, Borch-Johnsen K, Sandbaek A, Lauritzen T, Sorensen TI, et al. Non-replication of genome-wide based associations between common variants in INSIG2 and PFKP and obesity in studies of 18, 014 Danes. PLoS One. 2008;3(8):e2872.PubMedCrossRefGoogle Scholar
  124. 124.
    Brito EC, Lyssenko V, Renstrom F, Berglund G, Nilsson PM, Groop L, et al. Previously associated type 2 diabetes variants may interact with physical activity to modify the risk of impaired glucose regulation and type 2 diabetes: a study of 16, 003 Swedish adults. Diabetes. 2009;58(6):1411–8.PubMedCrossRefGoogle Scholar
  125. 125.
    Stephanie-May R, John WS, Tuomo R, Claude B, Marie-Claude V, Louis P. Interaction between HNF4A polymorphisms and physical activity in relation to type 2 diabetes-related traits: results from the Quebec Family Study. Diabetes Res Clin Pract. 2009;84(3):211–8.PubMedCrossRefGoogle Scholar
  126. 126.
    Kahara T, Takamura T, Hayakawa T, Nagai Y, Yamaguchi H, Katsuki T, et al. PPARgamma gene polymorphism is associated with exercise-mediated changes of insulin resistance in healthy men. Metabolism. 2003;52(2):209–12.PubMedCrossRefGoogle Scholar
  127. 127.
    Adamo KB, Sigal RJ, Williams K, Kenny G, Prud’homme D, Tesson F. Influence of Pro12Ala peroxisome proliferator-activated receptor gamma2 polymorphism on glucose response to exercise training in type 2 diabetes. Diabetologia. 2005;48(8):1503–9.PubMedCrossRefGoogle Scholar
  128. 128.
    Weiss EP, Kulaputana O, Ghiu IA, Brandauer J, Wohn CR, Phares DA, et al. Endurance training-induced changes in the insulin response to oral glucose are associated with the peroxisome proliferator-activated receptor-gamma2 Pro12Ala genotype in men but not in women. Metabolism. 2005;54(1):97–102.PubMedCrossRefGoogle Scholar
  129. 129.
    Lindi VI, Uusitupa MI, Lindstrom J, Louheranta A, Eriksson JG, Valle YY, et al. Association of the Pro12Ala polymorphism in the PPAR-gamma2 gene with 3-year incidence of type 2 diabetes and body weight change in the Finnish Diabetes Prevention Study. Diabetes. 2002;51(8):2581–6.PubMedCrossRefGoogle Scholar
  130. 130.
    Florez JC, Jablonski KA, Sun MW, Bayley N, Kahn SE, Shamoon H, et al. Effects of the type 2 diabetes-associated PPARG P12A polymorphism on progression to diabetes and response to troglitazone. J Clin Endocrinol Metab. 2007;92(4):1502–9.PubMedCrossRefGoogle Scholar
  131. 131.
    Franks PW, Jablonski KA, Delahanty L, Hanson RL, Kahn SE, Altshuler D, et al. The Pro12Ala variant at the peroxisome proliferator-activated receptor gamma gene and change in obesity-related traits in the Diabetes Prevention Program. Diabetologia. 2007;50(12):2451–60.PubMedCrossRefGoogle Scholar
  132. 132.
    Kilpelainen TO, Lakka TA, Laaksonen DE, Lindstrom J, Eriksson JG, Valle TT, et al. SNPs in PPARG associate with type 2 diabetes and interact with physical activity. Med Sci Sports Exerc. 2008;40(1):25–33.PubMedGoogle Scholar
  133. 133.
    Macho-Azcarate T, Marti A, Gonzalez A, Martinez JA, Ibanez J. Gln27Glu polymorphism in the beta2 adrenergic receptor gene and lipid metabolism during exercise in obese women. Int J Obes Relat Metab Disord. 2002;26(11):1434–41.PubMedCrossRefGoogle Scholar
  134. 134.
    Kilpelainen TO, Lakka TA, Laaksonen DE, Mager U, Salopuro T, Kubaszek A, et al. Interaction of single nucleotide polymorphisms in ADRB2, ADRB3, TNF, IL6, IGF1R, LIPC, LEPR, and GHRL with physical activity on the risk of type 2 diabetes mellitus and changes in characteristics of the metabolic syndrome: The Finnish Diabetes Prevention Study. Metabolism. 2008;57(3):428–36.PubMedCrossRefGoogle Scholar
  135. 135.
    Kahara T, Takamura T, Hayakawa T, Nagai Y, Yamaguchi H, Katsuki T, et al. Prediction of exercise-mediated changes in metabolic markers by gene polymorphism. Diabetes Res Clin Pract. 2002;57(2):105–10.PubMedCrossRefGoogle Scholar
  136. 136.
    Shiwaku K, Nogi A, Anuurad E, Kitajima K, Enkhmaa B, Shimono K, et al. Difficulty in losing weight by behavioral intervention for women with Trp64Arg polymorphism of the beta3-adrenergic receptor gene. Int J Obes Relat Metab Disord. 2003;27(9):1028–36.PubMedCrossRefGoogle Scholar
  137. 137.
    Salopuro T, Lindstrom J, Eriksson JG, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, et al. Common variants in beta2- and beta3-adrenergic receptor genes and uncoupling protein 1 as predictors of the risk for type 2 diabetes and body weight changes. The Finnish Diabetes Prevention Study. Clin Genet. 2004;66(4):365–7.PubMedCrossRefGoogle Scholar
  138. 138.
    Laaksonen DE, Siitonen N, Lindstrom J, Eriksson JG, Reunanen P, Tuomilehto J, et al. Physical activity, diet, and incident diabetes in relation to an ADRA2B polymorphism. Med Sci Sports Exerc. 2007;39(2):227–32.PubMedCrossRefGoogle Scholar
  139. 139.
    Todorova B, Kubaszek A, Pihlajamaki J, Lindström J, Eriksson J, Valle TT, et al. The G-250A promoter polymorphism of the hepatic lipase gene predicts the conversion from impaired glucose tolerance to type 2 diabetes mellitus: the Finnish Diabetes Prevention Study. J Clin Endocrinol Metab. 2004;89(5):2019–23.PubMedCrossRefGoogle Scholar
  140. 140.
    Hagberg JM, Ferrell RE, Katzel LI, Dengel DR, Sorkin JD, Goldberg AP. Apolipoprotein E genotype and exercise training-induced increases in plasma high-density lipoprotein (HDL)- and HDL2-cholesterol levels in overweight men. Metabolism. 1999;48(8):943–5.PubMedCrossRefGoogle Scholar
  141. 141.
    Garenc C, Perusse L, Bergeron J, Gagnon J, Chagnon YC, Borecki IB, et al. Evidence of LPL gene-exercise interaction for body fat and LPL activity: the HERITAGE Family Study. J Appl Physiol. 2001;91(3):1334–40.PubMedGoogle Scholar
  142. 142.
    Florez JC, Jablonski KA, Bayley N, Pollin TI, de Bakker PIW, Shuldiner AR, et al. TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med. 2006;355(3):241–50.PubMedCrossRefGoogle Scholar
  143. 143.
    Franks PW, Jablonski KA, Delahanty LM, McAteer JB, Kahn SE, Knowler WC, et al. Assessing gene-treatment interactions at the FTO and INSIG2 loci on obesity-related traits in the Diabetes Prevention Program. Diabetologia. 2008;51(12):2214–23.PubMedCrossRefGoogle Scholar
  144. 144.
    Lappalainen TJ, Tolppanen AM, Kolehmainen M, Schwab U, Lindström J, Tuomilehto J, et al. The common variant in the FTO gene did not modify the effect of lifestyle changes on body weight: the Finnish Diabetes Prevention Study. Obesity (Silver Spring). 2009;17(4):832–6.CrossRefGoogle Scholar
  145. 145.
    Hakanen M, Raitakari OT, Lehtimaki T, Peltonen N, Pahkala K, Sillanmäki L, et al. FTO genotype is associated with body mass index after the age of seven years but not with energy intake or leisure-time physical activity. J Clin Endocrinol Metab. 2009;94(4):1281–7.PubMedCrossRefGoogle Scholar
  146. 146.
    Kilpelainen TO, Lakka TA, Laaksonen DE, Laukkanen O, Lindström J, Eriksson JG, et al. Physical activity modifies the effect of SNPs in the SLC2A2 (GLUT2) and ABCC8 (SUR1) genes on the risk of developing type 2 diabetes. Physiol Genomics. 2007;31(2):264–72.PubMedCrossRefGoogle Scholar
  147. 147.
    Moore AF, Jablonski KA, McAteer JB, Saxena R, Pollin TI, Franks PW, et al. Extension of type 2 diabetes genome-wide association scan results in the diabetes prevention program. Diabetes. 2008;57(9):2503–10.PubMedCrossRefGoogle Scholar
  148. 148.
    Moore AF, Jablonski KA, Mason CC, McAteer JB, Goldstein BJ, Kahn SE, et al. The association of ENPP1 K121Q with diabetes incidence is abolished by lifestyle modification in the diabetes prevention program. J Clin Endocrinol Metab. 2009;94(2):449–55.PubMedCrossRefGoogle Scholar
  149. 149.
    Wong MY, Day NE, Luan JA, Chan KP, Wareham NJ. The detection of gene-environment interaction for continuous traits: should we deal with measurement error by bigger studies or better measurement? Int J Epidemiol. 2003;32(1):51–7.PubMedCrossRefGoogle Scholar
  150. 150.
    Smith PG, Day NE. The design of case-control studies: the influence of confounding and interaction effects. Int J Epidemiol. 1984;13(3):356–65.PubMedCrossRefGoogle Scholar
  151. 151.
    Luan JA, Wong MY, Day NE, Wareham NJ. Sample size determination for studies of gene-environment interaction. Int J Epidemiol. 2001;30(5):1035–40.PubMedCrossRefGoogle Scholar
  152. 152.
    Wareham NJ, Jakes RW, Rennie KL, Mitchell J, Hennings S, Day NE. Validity and repeatability of the EPIC-Norfolk Physical Activity Questionnaire. Int J Epidemiol. 2002;31(1):168–74.PubMedCrossRefGoogle Scholar
  153. 153.
    Friedenreich CM, Courneya KS, Neilson HK, Matthews CE, Willis G, Irwin M, et al. Reliability and validity of the Past Year Total Physical Activity Questionnaire. Am J Epidemiol. 2006;163(10):959–70.PubMedCrossRefGoogle Scholar
  154. 154.
    Trost SG, Way R, Okely AD. Predictive validity of three ActiGraph energy expenditure equations for children. Med Sci Sports Exerc. 2006;38(2):380–7.PubMedCrossRefGoogle Scholar
  155. 155.
    Ceesay SM, Prentice AM, Day KC, Murgatroyd PR, Goldberg GR, Scott W, et al. The use of heart rate monitoring in the estimation of energy expenditure: a validation study using indirect whole-body calorimetry. Br J Nutr. 1989;61(2):175–86.PubMedCrossRefGoogle Scholar
  156. 156.
    Brage S, Ekelund U, Brage N, Hennings MA, Froberg K, Franks PW, et al. Hierarchy of individual calibration levels for heart rate and accelerometry to measure physical activity. J Appl Physiol. 2007;103(2):682–92.PubMedCrossRefGoogle Scholar
  157. 157.
    Wareham NJ, Young EH, Loos RJ. Epidemiological study designs to investigate gene-behavior interactions in the context of human obesity. Obesity (Silver Spring). 2008;16 Suppl 3:S66–71.CrossRefGoogle Scholar
  158. 158.
    Balding DJ. A tutorial on statistical methods for population association studies. Nat Rev Genet. 2006;7(10):781–91.PubMedCrossRefGoogle Scholar
  159. 159.
    Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I. Controlling the false discovery rate in behavior genetics research. Behav Brain Res. 2001;125(1–2):279–84.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Division of MedicineUmeå University HospitalUmeåSweden

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