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.

Association between fat intake, physical activity and mortality depending on genetic variation in FTO

“…[12][13][14][15]31 Our results indicating that the level of physical activity especially modifies the increase in fat mass, and not lean body mass, by FTO are important. Although individuals with higher physical activity level have lower percentage body fat, the association between FTO and percentage body fat was neutralized only among the 20% individuals with highest level of physical activity.…”

“…11 Several studies have also observed an interaction between physical activity and FTO genotype on the risk of obesity. [12][13][14][15] There may in a similar manner be an interaction between fat intake, or physical activity, and FTO genotype on mortality. The aim of this study was to examine the association between the FTO genotype and cause-specific mortality, and to study the association between fat intake, or physical activity, and mortality depending on FTO genotype.…”

Lifestyle factors modify obesity risk linked to PPARG2 and FTO variants in an elderly population: a cross-sectional analysis in the SUN Project

“…Some research work which reported the combined effect of PPARG and ADRB3 or ACE I/D gene variants for increasing BMI (Huang et al 2011;Passaro et al 2011) stated that the combined effect of FTO and MC4R genetic variants was strongly associated with obesity risk and BMI. Similarly, Cauchi et al (2009) observed that these two genetic variants increased obesity risk by 24 %, and low PA levels did accentuate this effect. Our study showed that the effect of PPARG2 (Ala12 allele) and FTO (rs9939609) gene variants on obesity effect might depend on high CHO intake.…”

Common genetic variation near MC4R is associated with eating behaviour patterns in European populations

“…Both SNPs were associated with BMI increase at 16 years in the Finnish population (P ¼ 0.002 and 2 Â 10 À8 ) 29 and at baseline in the French middle-aged population (P ¼ 0.05 and 0.006). 29 We then analysed the associations of rs17782313 and rs1421085 with snacking and bulimia/ eating large amounts of food in these cohorts.…”

“…Both SNPs were associated with BMI increase at 16 years in the Finnish population (P ¼ 0.002 and 2 Â 10 À8 ) 29 and at baseline in the French middle-aged population (P ¼ 0.05 and 0.006). 29 We then analysed the associations of rs17782313 and rs1421085 with snacking and bulimia/ eating large amounts of food in these cohorts. Among the Finnish young population, we observed a tendency to snack more during weekends for individuals carrying the MC4R rs17782313-C allele (TT: 78.0%, CT: 79.5%, CC: 85.3%, P ¼ 0.040; Table 2) but not for the FTO rs1421085-C carriers.…”