title: Combined effects of MC4R and FTO common genetic variants on obesity in European general populations.
abstract: Genome-wide association scans recently identified common polymorphisms, in intron 1 of FTO and 188 kb downstream MC4R, that modulate body mass index (BMI) and associate with increased risk of obesity. Although their individual contribution to obesity phenotype is modest, their combined effects and their interactions with environmental factors remained to be evaluated in large general populations from birth to adulthood. In the present study, we analyzed independent and combined effects of the FTO rs1421085 and MC4R rs17782313 risk alleles on BMI, fat mass, prevalence and incidence of obesity and subsequent type 2 diabetes (T2D) as well as their interactions with physical activity levels and gender in two European prospective population-based cohorts of 4,762 Finnish adolescents (NFBC 1986) and 3,167 French adults (D.E.S.I.R.). Compared to participants carrying neither FTO nor MC4R risk allele (20-24% of the populations), subjects with three or four risk alleles (7-10% of the populations) had a 3-fold increased susceptibility of developing obesity during childhood. In adults, their combined effects were more modest (approximately 1.8-fold increased risk) and associated with a 1.27% increase in fat mass (P = 0.001). Prospectively, we demonstrated that each FTO and MC4R risk allele increased obesity and T2D incidences by 24% (P = 0.02) and 21% (P = 0.02), respectively. However, the effect on T2D disappeared after adjustment for BMI. The Z-BMI and ponderal index of newborns homozygous for the rs1421085 C allele were 0.1 units (P = 0.02) and 0.27 g/cm(3) (P = 0.005) higher, respectively, than in those without FTO risk allele. The MC4R rs17782313 C allele was more associated with obesity and fat mass deposition in males than in females (P = 0.003 and P = 0.03, respectively) and low physical activity accentuated the effect of the FTO polymorphism on BMI increase and obesity prevalence (P = 0.008 and P = 0.01, respectively). In European general populations, the combined effects of common polymorphisms in FTO and MC4R are therefore additive, predictive of obesity and T2D, and may be influenced by interactions with physical activity levels and gender, respectively.
authors.affiliation: CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Cauchi
authors.forename: Fanny
authors.initials: F
authors.lastname: Stutzmann
authors.forename: Christine
authors.initials: C
authors.lastname: Cavalcanti-Proença
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Durand
authors.forename: Anneli
authors.initials: A
authors.lastname: Pouta
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Hartikainen
authors.forename: Michel
authors.initials: M
authors.lastname: Marre
authors.forename: Sylviane
authors.initials: S
authors.lastname: Vol
authors.forename: Tuija
authors.initials: T
authors.lastname: Tammelin
authors.forename: Jaana
authors.initials: J
authors.lastname: Laitinen
authors.forename: Arturo
authors.initials: A
authors.lastname: Gonzalez-Izquierdo
authors.forename: Alexandra I F
authors.initials: AI
authors.lastname: Blakemore
authors.forename: Paul
authors.initials: P
authors.lastname: Elliott
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Järvelin
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D015992:Body Mass Index; D002648:Child; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005387:Finland / Q000453:epidemiology; D005602:France / Q000453:epidemiology; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D011506:Proteins / Q000235:genetics*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*; D012307:Risk Factors
chemical_list: C470072:MC4R protein, human; D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human