Physical activity attenuates the genetic predisposition to obesity in 20,000 men and women from EPIC-Norfolk prospective population study.
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.
Li
Shengxu
S
MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, United Kingdom.
Zhao
Jing Hua
JH
Luan
Jian'an
J
Ekelund
Ulf
U
Luben
Robert N
RN
Khaw
Kay-Tee
KT
Wareham
Nicholas J
NJ
Loos
Ruth J F
RJ
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*
PLoS One. 2007 Dec 26;2(12):e1361
18159244
Science. 2007 May 11;316(5826):889-94
17434869
Int J Obes (Lond). 2009 Jan;33(1):29-36
19048013
Arch Intern Med. 2008 Sep 8;168(16):1791-7
18779467
Obesity (Silver Spring). 2008 Dec;16 Suppl 3:S5-S10
19037213
Nat Genet. 2009 Jan;41(1):25-34
19079261
J Mol Med (Berl). 2009 May;87(5):537-46
19255736
Int J Epidemiol. 1997;26 Suppl 1:S6-14
9126529
Am J Clin Nutr. 2009 Aug;90(2):425-8
19553294
Diabetologia. 2009 Jul;52(7):1334-8
19373445
Med Sci Sports Exerc. 2008 Nov;40(11):1909-15
18845964
J Clin Endocrinol Metab. 2009 Apr;94(4):1281-7
19158205
Nat Genet. 2009 Jan;41(1):18-24
19079260
Stat Med. 2004 Mar 30;23(6):987-98
15027084
Behav Genet. 1997 Jul;27(4):325-51
9519560
Diabetes. 2008 Jan;57(1):95-101
17942823
Am J Clin Nutr. 2010 Jan;91(1):184-90
19812171
PLoS Genet. 2007 Jul;3(7):e115
17658951
Public Health Nutr. 2006 Oct;9(7):851-8
17010250
Br J Cancer. 1999 Jul;80 Suppl 1:95-103
10466767
Nat Genet. 2008 Jun;40(6):768-75
18454148
Am J Clin Nutr. 2009 Nov;90(5):1418-25
19726594
Am J Clin Nutr. 2009 Apr;89(4):1011-8
19225119
Diabetes Care. 2007 Aug;30(8):2101-6
17536069
Int J Epidemiol. 2001 Oct;30(5):1035-40
11689518
Int J Epidemiol. 2003 Feb;32(1):51-7
12690008
Am J Clin Nutr. 2009 Oct;90(4):1096-103
19710197
Int J Epidemiol. 2006 Aug;35(4):1034-43
16709620
Diabetes. 2008 Oct;57(10):2851-7
18599522
Obesity (Silver Spring). 2009 Apr;17(4):832-6
19180072
Epidemiol Rev. 2007;29:129-43
17533172
Public Health Nutr. 2003 Jun;6(4):407-13
12795830
Endocr Rev. 2006 Dec;27(7):750-61
17122359
Nature. 2009 Oct 8;461(7265):747-53
19812666