Statistical and Biological Gene-Lifestyle Interactions of MC4R and FTO with Diet and Physical Activity on Obesity: New Effects on Alcohol Consumption

Abstract

BackgroundFat mass and obesity (FTO) and melanocortin-4 receptor (MC4R) and are relevant genes associated with obesity. This could be through food intake, but results are contradictory. Modulation by diet or other lifestyle factors is also not well understood.ObjectiveTo investigate whether MC4R and FTO associations with body-weight are modulated by diet and physical activity (PA), and to study their association with alcohol and food intake.MethodsAdherence to Mediterranean diet (AdMedDiet) and physical activity (PA) were assessed by validated questionnaires in 7,052 high cardiovascular risk subjects. MC4R rs17782313 and FTO rs9939609 were determined. Independent and joint associations (aggregate genetic score) as well as statistical and biological gene-lifestyle interactions were analyzed.ResultsFTO rs9939609 was associated with higher body mass index (BMI), waist circumference (WC) and obesity (P<0.05 for all). A similar, but not significant trend was found for MC4R rs17782313. Their additive effects (aggregate score) were significant and we observed a 7% per-allele increase of being obese (OR = 1.07; 95%CI 1.01–1.13). We found relevant statistical interactions (P<0.05) with PA. So, in active individuals, the associations with higher BMI, WC or obesity were not detected. A biological (non-statistical) interaction between AdMedDiet and rs9939609 and the aggregate score was found. Greater AdMedDiet in individuals carrying 4 or 3-risk alleles counterbalanced their genetic predisposition, exhibiting similar BMI (P = 0.502) than individuals with no risk alleles and lower AdMedDiet. They also had lower BMI (P = 0.021) than their counterparts with low AdMedDiet. We did not find any consistent association with energy or macronutrients, but found a novel association between these polymorphisms and lower alcohol consumption in variant-allele carriers (B+/−SE: −0.57+/−0.16 g/d per-score-allele; P = 0.001).ConclusionStatistical and biological interactions with PA and diet modulate the effects of FTO and MC4R polymorphisms on obesity. The novel association with alcohol consumption seems independent of their effects on BMI.

The importance of gene–environment interactions in human obesity

“…Using a multiple linear regression model with the inclusion of a cross-product term signifying the product of environmental (E) and genetic (G) variables is the most common method to assess interactions [107,114,117,125]. Coding genetic polymorphisms is either performed to create a binary variable (under a recessive or dominant model) or a three-category variable based on an additive model, with the latter often used when the true functional model of a given marker is not known [261].…”

“…The value of improving measurement accuracy as opposed to increasing sample size can be reinforced with the example of physical activity measurement, a common exposure analysed in gene-environment interactions of obesity [117,125,269]. Physical activity is usually assessed by questionnaire, and even comprehensive instruments that address occupational and leisure activity rarely correlate with objective measures of energy expenditure above 0.3 [321].…”

Mediterranean Diet and Cardiovascular Health: Teachings of the PREDIMED Study

“…Continuing with the classic polymorphisms, we analyzed the influence of the MeDiet and fat intake on the effects of CETP polymorphisms (24502C > T and the TaqIB) on lipids (44). In another study, we focused on gene-diet interactions determining obesity (45). A genetic score, including the melanocortin 4 receptor (MC4R) rs17782313 and fat mass and obesity (FTO) rs9939609 variants, was strongly associated with BMI; although there was no statistically significant interaction with the MeDiet, greater adherence significantly reduced BMI in genetically susceptible individuals.…”

Rola genu podatności na otyłość (FTO) w rozwoju otyłości — przegląd

“…In line with these results, A-allele carriers were reported to consume more meals per day and eat more energy dense foods [62]. However, in study of Corella et al [63], no association between FTO and general food intake or food groups was found, but alcohol consumption in variant allele carriers was significantly lower than in wild-type subjects. Interestingly, AA genotype subjects presented also the highest rate of under-reporting of energy intake (17%) compared to TT genotype (15.4%), which was also more frequent in obese population [61].…”

“…For example, Razquin et al [66] have demonstrated that a Mediterranean-based diet, rich in mono-and polyunsaturated fat, provides FTO risk allele carriers some protection against body weight gain after three years of nutritional intervention. Also Corella et al showed that high adherence to a Mediterranean diet can counterbalance the genetic susceptibility to obesity [63]. In the Malmo Diet and Cancer Study, fat intake was shown to accentuate the effect of FTO on obesity.…”