title: Physical activity attenuates the genetic predisposition to obesity in 20,000 men and women from EPIC-Norfolk prospective population study.
abstract: BACKGROUND
  We have previously shown that multiple genetic loci identified by genome-wide association studies (GWAS) increase the susceptibility to obesity in a cumulative manner. It is, however, not known whether and to what extent this genetic susceptibility may be attenuated by a physically active lifestyle. We aimed to assess the influence of a physically active lifestyle on the genetic predisposition to obesity in a large population-based study.
  
  
  RESULTS
  We genotyped 12 SNPs in obesity-susceptibility loci in a population-based sample of 20,430 individuals (aged 39-79 y) from the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort with an average follow-up period of 3.6 y. A genetic predisposition score was calculated for each individual by adding the body mass index (BMI)-increasing alleles across the 12 SNPs. Physical activity was assessed using a self-administered questionnaire. Linear and logistic regression models were used to examine main effects of the genetic predisposition score and its interaction with physical activity on BMI/obesity risk and BMI change over time, assuming an additive effect for each additional BMI-increasing allele carried. Each additional BMI-increasing allele was associated with 0.154 (standard error [SE] 0.012) kg/m(2) (p = 6.73 x 10(-37)) increase in BMI (equivalent to 445 g in body weight for a person 1.70 m tall). This association was significantly (p(interaction) = 0.005) more pronounced in inactive people (0.205 [SE 0.024] kg/m(2) [p = 3.62 x 10(-18); 592 g in weight]) than in active people (0.131 [SE 0.014] kg/m(2) [p = 7.97 x 10(-21); 379 g in weight]). Similarly, each additional BMI-increasing allele increased the risk of obesity 1.116-fold (95% confidence interval [CI] 1.093-1.139, p = 3.37 x 10(-26)) in the whole population, but significantly (p(interaction) = 0.015) more in inactive individuals (odds ratio [OR] = 1.158 [95% CI 1.118-1.199; p = 1.93 x 10(-16)]) than in active individuals (OR = 1.095 (95% CI 1.068-1.123; p = 1.15 x 10(-12)]). Consistent with the cross-sectional observations, physical activity modified the association between the genetic predisposition score and change in BMI during follow-up (p(interaction) = 0.028).
  
  
  CONCLUSIONS
  Our study shows that living a physically active lifestyle is associated with a 40% reduction in the genetic predisposition to common obesity, as estimated by the number of risk alleles carried for any of the 12 recently GWAS-identified loci. Please see later in the article for the Editors' Summary.
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, United Kingdom.
authors.forename: Shengxu
authors.initials: S
authors.lastname: Li
authors.forename: Jing Hua
authors.initials: JH
authors.lastname: Zhao
authors.forename: Jian'an
authors.initials: J
authors.lastname: Luan
authors.forename: Ulf
authors.initials: U
authors.lastname: Ekelund
authors.forename: Robert N
authors.initials: RN
authors.lastname: Luben
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Ruth J F
authors.initials: RJ
authors.lastname: Loos
mesh_terms: D000328:Adult; D000368:Aged; D015992:Body Mass Index; D001835:Body Weight / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics* / Q000517:prevention & control; D006801:Humans; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000235:genetics*; D009765:Obesity / Q000453:epidemiology / Q000235:genetics* / Q000517:prevention & control*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011159:Population Surveillance; D011446:Prospective Studies; D006113:United Kingdom / Q000453:epidemiology; D044465:White People / Q000235:genetics*
references.citation: PLoS One. 2007 Dec 26;2(12):e1361
references.pmid: 18159244
references.citation: Science. 2007 May 11;316(5826):889-94
references.pmid: 17434869
references.citation: Int J Obes (Lond). 2009 Jan;33(1):29-36
references.pmid: 19048013
references.citation: Arch Intern Med. 2008 Sep 8;168(16):1791-7
references.pmid: 18779467
references.citation: Obesity (Silver Spring). 2008 Dec;16 Suppl 3:S5-S10
references.pmid: 19037213
references.citation: Nat Genet. 2009 Jan;41(1):25-34
references.pmid: 19079261
references.citation: J Mol Med (Berl). 2009 May;87(5):537-46
references.pmid: 19255736
references.citation: Int J Epidemiol. 1997;26 Suppl 1:S6-14
references.pmid: 9126529
references.citation: Am J Clin Nutr. 2009 Aug;90(2):425-8
references.pmid: 19553294
references.citation: Diabetologia. 2009 Jul;52(7):1334-8
references.pmid: 19373445
references.citation: Med Sci Sports Exerc. 2008 Nov;40(11):1909-15
references.pmid: 18845964
references.citation: J Clin Endocrinol Metab. 2009 Apr;94(4):1281-7
references.pmid: 19158205
references.citation: Nat Genet. 2009 Jan;41(1):18-24
references.pmid: 19079260
references.citation: Stat Med. 2004 Mar 30;23(6):987-98
references.pmid: 15027084
references.citation: Behav Genet. 1997 Jul;27(4):325-51
references.pmid: 9519560
references.citation: Diabetes. 2008 Jan;57(1):95-101
references.pmid: 17942823
references.citation: Am J Clin Nutr. 2010 Jan;91(1):184-90
references.pmid: 19812171
references.citation: PLoS Genet. 2007 Jul;3(7):e115
references.pmid: 17658951
references.citation: Public Health Nutr. 2006 Oct;9(7):851-8
references.pmid: 17010250
references.citation: Br J Cancer. 1999 Jul;80 Suppl 1:95-103
references.pmid: 10466767
references.citation: Nat Genet. 2008 Jun;40(6):768-75
references.pmid: 18454148
references.citation: Am J Clin Nutr. 2009 Nov;90(5):1418-25
references.pmid: 19726594
references.citation: Am J Clin Nutr. 2009 Apr;89(4):1011-8
references.pmid: 19225119
references.citation: Diabetes Care. 2007 Aug;30(8):2101-6
references.pmid: 17536069
references.citation: Int J Epidemiol. 2001 Oct;30(5):1035-40
references.pmid: 11689518
references.citation: Int J Epidemiol. 2003 Feb;32(1):51-7
references.pmid: 12690008
references.citation: Am J Clin Nutr. 2009 Oct;90(4):1096-103
references.pmid: 19710197
references.citation: Int J Epidemiol. 2006 Aug;35(4):1034-43
references.pmid: 16709620
references.citation: Diabetes. 2008 Oct;57(10):2851-7
references.pmid: 18599522
references.citation: Obesity (Silver Spring). 2009 Apr;17(4):832-6
references.pmid: 19180072
references.citation: Epidemiol Rev. 2007;29:129-43
references.pmid: 17533172
references.citation: Public Health Nutr. 2003 Jun;6(4):407-13
references.pmid: 12795830
references.citation: Endocr Rev. 2006 Dec;27(7):750-61
references.pmid: 17122359
references.citation: Nature. 2009 Oct 8;461(7265):747-53
references.pmid: 19812666