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Assessing gene-environment interaction effects of FTO, MC4R and lifestyle factors on obesity using an extreme phenotype sampling design: Results from the HUNT study

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ABSTRACT

Background: Our aim was to assess the influence of age, gender and lifestyle factors on the effect of the obesity-promoting alleles of FTO and MCR4.

Methods: The HUNT study comprises health information on the population of Nord-Trøndelag county, Norway. Extreme phenotype participants (gender-wise lower and upper quartiles of waist-hip-ratio and BMI ≥ 35 kg/m2) in the third survey, HUNT3 (2006–08), were genotyped for the single-nucleotide polymorphisms rs9939609 (FTO) and rs17782313 (MC4R); 25686 participants were successfully genotyped. Extreme sampling was chosen to increase power to detect genetic and gene-environment effects on waist-hip-ratio and BMI. Statistical inference was based on linear regression models and a missing-covariate likelihood approach for the extreme phenotype sampling design. Environmental factors were physical activity, diet (artificially sweetened beverages) and smoking. Longitudinal analysis was performed using material from HUNT2 (1995–97).

Results: Cross-sectional and longitudinal genetic effects indicated stronger genetic associations with obesity in young than in old, as well as differences between women and men. We observed larger genetic effects among physically inactive compared to active individuals. This interaction was age-dependent and seen mainly in 20–40 year olds. We observed a greater FTO effect among men with a regular intake of artificially sweetened beverages, compared to non-drinkers. Interaction analysis of smoking was mainly inconclusive.

Conclusions: In a large all-adult and area-based population survey the effects of obesity-promoting minor-alleles of FTO and MCR4, and interactions with life style factors are age- and gender-related. These findings appear relevant when designing individualized treatment for and prophylaxis against obesity.

No MeSH data available.


Gene-environment interaction effects.Estimated WHR (a) and BMI (b) in the 20–40 years age group for all FTO genotypes and for increasing levels of physical activity (PA) for an average man (age 31, ASB 4.2, PCYR 1.8) and woman (age 31, ASB 4.7, PCYR 2.1). Estimated BMI in the 40–60 years age group for all FTO genotypes for increasing levels of intake of artificially sweetened beverages (c) and increasing number of pack years (d) for an average man (age 51, PA 4.2, ASB 2.7, PCYR 7.4) and woman (age 49, PA 4.3, ASB 2.7, PCYR 7.1).
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pone.0175071.g003: Gene-environment interaction effects.Estimated WHR (a) and BMI (b) in the 20–40 years age group for all FTO genotypes and for increasing levels of physical activity (PA) for an average man (age 31, ASB 4.2, PCYR 1.8) and woman (age 31, ASB 4.7, PCYR 2.1). Estimated BMI in the 40–60 years age group for all FTO genotypes for increasing levels of intake of artificially sweetened beverages (c) and increasing number of pack years (d) for an average man (age 51, PA 4.2, ASB 2.7, PCYR 7.4) and woman (age 49, PA 4.3, ASB 2.7, PCYR 7.1).

Mentions: Estimated parameters from modelling interaction effects between FTO and MC4R and physical activity are presented in Table 2. For both men and women 20–40 years, we found that the interaction between physical activity and FTO was associated with WHR (FDR-adjusted p-value < 0.05). For women 20–40 years, we also found that both the interactions between FTO and physical activity, and MC4R and physical activity were associated with BMI. Consider a man 20–40 years with one copy of the FTO minor-allele. In our regression model for WHR with interactions (Model (3)) we estimated βFTO = 0.017 and βFTO*PA = −0.0029 (Table 2). Thus, with physical activity index 5 or greater, we see that the effect of one FTO minor-allele was cancelled out by the interaction between FTO and physical activity. In Fig 3a we have plotted estimated WHR against increasing levels of physical activity for an average man and woman 20–40 years for the three genotypes of FTO. Similarly, estimated BMI is presented in Fig 3b. Estimated WHR or BMI was quite similar for individuals with high levels of physical activity, regardless of FTO genotype. For individuals with low levels of physical activity, those with one or two copies of the FTO minor-allele had higher estimated WHR or BMI than those with no minor-allele. In other words, the over-all effect of FTO on obesity was negligible in highly active individuals aged between 20 and 40 years.


Assessing gene-environment interaction effects of FTO, MC4R and lifestyle factors on obesity using an extreme phenotype sampling design: Results from the HUNT study
Gene-environment interaction effects.Estimated WHR (a) and BMI (b) in the 20–40 years age group for all FTO genotypes and for increasing levels of physical activity (PA) for an average man (age 31, ASB 4.2, PCYR 1.8) and woman (age 31, ASB 4.7, PCYR 2.1). Estimated BMI in the 40–60 years age group for all FTO genotypes for increasing levels of intake of artificially sweetened beverages (c) and increasing number of pack years (d) for an average man (age 51, PA 4.2, ASB 2.7, PCYR 7.4) and woman (age 49, PA 4.3, ASB 2.7, PCYR 7.1).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5383228&req=5

pone.0175071.g003: Gene-environment interaction effects.Estimated WHR (a) and BMI (b) in the 20–40 years age group for all FTO genotypes and for increasing levels of physical activity (PA) for an average man (age 31, ASB 4.2, PCYR 1.8) and woman (age 31, ASB 4.7, PCYR 2.1). Estimated BMI in the 40–60 years age group for all FTO genotypes for increasing levels of intake of artificially sweetened beverages (c) and increasing number of pack years (d) for an average man (age 51, PA 4.2, ASB 2.7, PCYR 7.4) and woman (age 49, PA 4.3, ASB 2.7, PCYR 7.1).
Mentions: Estimated parameters from modelling interaction effects between FTO and MC4R and physical activity are presented in Table 2. For both men and women 20–40 years, we found that the interaction between physical activity and FTO was associated with WHR (FDR-adjusted p-value < 0.05). For women 20–40 years, we also found that both the interactions between FTO and physical activity, and MC4R and physical activity were associated with BMI. Consider a man 20–40 years with one copy of the FTO minor-allele. In our regression model for WHR with interactions (Model (3)) we estimated βFTO = 0.017 and βFTO*PA = −0.0029 (Table 2). Thus, with physical activity index 5 or greater, we see that the effect of one FTO minor-allele was cancelled out by the interaction between FTO and physical activity. In Fig 3a we have plotted estimated WHR against increasing levels of physical activity for an average man and woman 20–40 years for the three genotypes of FTO. Similarly, estimated BMI is presented in Fig 3b. Estimated WHR or BMI was quite similar for individuals with high levels of physical activity, regardless of FTO genotype. For individuals with low levels of physical activity, those with one or two copies of the FTO minor-allele had higher estimated WHR or BMI than those with no minor-allele. In other words, the over-all effect of FTO on obesity was negligible in highly active individuals aged between 20 and 40 years.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Our aim was to assess the influence of age, gender and lifestyle factors on the effect of the obesity-promoting alleles of FTO and MCR4.

Methods: The HUNT study comprises health information on the population of Nord-Tr&oslash;ndelag county, Norway. Extreme phenotype participants (gender-wise lower and upper quartiles of waist-hip-ratio and BMI &ge; 35 kg/m2) in the third survey, HUNT3 (2006&ndash;08), were genotyped for the single-nucleotide polymorphisms rs9939609 (FTO) and rs17782313 (MC4R); 25686 participants were successfully genotyped. Extreme sampling was chosen to increase power to detect genetic and gene-environment effects on waist-hip-ratio and BMI. Statistical inference was based on linear regression models and a missing-covariate likelihood approach for the extreme phenotype sampling design. Environmental factors were physical activity, diet (artificially sweetened beverages) and smoking. Longitudinal analysis was performed using material from HUNT2 (1995&ndash;97).

Results: Cross-sectional and longitudinal genetic effects indicated stronger genetic associations with obesity in young than in old, as well as differences between women and men. We observed larger genetic effects among physically inactive compared to active individuals. This interaction was age-dependent and seen mainly in 20&ndash;40 year olds. We observed a greater FTO effect among men with a regular intake of artificially sweetened beverages, compared to non-drinkers. Interaction analysis of smoking was mainly inconclusive.

Conclusions: In a large all-adult and area-based population survey the effects of obesity-promoting minor-alleles of FTO and MCR4, and interactions with life style factors are age- and gender-related. These findings appear relevant when designing individualized treatment for and prophylaxis against obesity.

No MeSH data available.