Common variants near MC4R in relation to body fat, body fat distribution, metabolic traits and energy expenditure.

OBJECTIVE: Common variants near melanocortin receptor 4 (MC4R) have been related to fatness and type 2 diabetes. We examined the associations of rs17782313 and rs17700633 in relation to body fat, body fat distribution, metabolic traits, weight development and energy expenditure. METHODS: Obese young men (n = 753, BMI > or = 31.0 kg m(-2)) and a randomly selected group (n = 874) identified from a population of 174 800 men were re-examined in three surveys at mean ages 35, 46 and 49 years (S-35, S-46 and S-49). Measurements were available at upto eight times from birth to adulthood. Logistic regression analysis was used to assess odds ratio (OR) for the presence of the carrier allele for a given difference in phenotypic values. RESULTS: Rs17782313 minor C-allele was associated with overall, abdominal and peripheral fatness (range of OR = 1.06-1.14 per z-score units) at all three surveys, although only consistently significant at S-35 and S-46. Rs17700633 minor A-allele was also associated with the fatness measures, but significantly so only at S-49 for overall and abdominal fatness (range of OR = 1.03-1.15 per z-score units), and peripheral fatness (OR = 1.15-1.20 per z-score units). There were only few significant associations with metabolic traits. The rs17782313 C-allele and the rs17700633 A-allele were both associated with lower high-density lipoprotein cholesterol (range of OR = 0.64-0.84 per mol l(-1)), significantly at S-46. The rs17700633 A-allele was significantly associated with insulin (OR = 1.25 per 50 pmol l(-1)), leptin (OR = 1.42 per 10 ng microl(-1)) and insulin sensitivity (OR = 0.81 per model unit). The rs17782313 C-allele and the rs17700633 A-allele were both associated with BMI in childhood and adolescence (range of OR = 1.04-1.17 per z-score units), significant for the rs17782313 C-allele at the age of 13-19 years and for rs17700633 A-allele at age 7, 10, 13 and 19 years. No significant associations were found for energy expenditure. CONCLUSION: Near MC4R variants appear to contribute to body fat, body fat distribution, some metabolic traits, weight development during childhood, but not to energy expenditure.

Impact on weight dynamics and general growth of the common FTO rs9939609: a longitudinal Danish cohort study.

OBJECTIVE AND DESIGN: We investigated the impact of the fatness-related FTO rs9939609 A-allele on cross-sectional and longitudinal measures of body mass index (BMI), height and lean body mass (LBM) in a unique cohort representing a broad range of BMI. SUBJECTS AND MEASUREMENTS: A random sample of all men attending the Danish draft boards during 1943-1977 plus all men with a BMI>or=31.0 kg/m(2) (assuring representation of the right end of the distribution) was taken. Anthropometric measures were available at up to eight points in time from birth to adulthood in 1629 genotyped men. The odds ratio (OR) for being a carrier of FTO rs9939609 according to (1) one unit alteration in z-scores for BMI, height and LBM at given ages and (2) longitudinal changes in BMI and height z-scores were assessed by logistic regression. RESULTS: Except at birth, the AA genotype was associated with increased BMI z-scores at all point during the monitored lifespan, starting at the age of 7 years. This effect remained stable until early adulthood, where further weight gain occurred. The AA genotype was also--mainly through the effect on fatness--associated with accelerated linear growth in childhood (age 7 years; OR, 1.36; 95% confidence interval (CI), 1.06-1.74) and increased LBM in adulthood (OR, 1.24; 95% CI, 1.14-1.35). CONCLUSION: Fatness induced by FTO rs9939609 in early childhood is sustained until early adulthood, where further weight gain may occur. FTO rs9939609 may, however, also be associated with linear growth and LBM mainly through the effect on fat mass.

Lack of association of fatness-related FTO gene variants with energy expenditure or physical activity.

CONTEXT: A common variant in the first intron of FTO (rs9939609, T/A) is associated with fatness in Caucasians. OBJECTIVE: FTO may regulate energy homeostasis through the hypothalamus, and we hypothesized that AA-genotypes of rs9939609 FTO have lower energy expenditure and/or a lower level of physical activity. METHODS: The study population included all obese young men (body mass index > or = 31 kg/m(2)) at the mandatory draft board examinations in the Copenhagen area from 1943 to 1977 and a randomly selected control group from this population. Subgroups of 234 obese and 323 controls were examined in 1998-2000 (median age 48 yr). Fat mass (FM), lean body mass (LBM), leisure-time physical activity (LTPA), maximum oxygen uptake (VO(2)max), resting energy expenditure (REE), and glucose-induced thermogenesis (GIT) were measured. The FTO rs9939609 variant was genotyped. A recessive transmission mode fit the data best. Logistic regression was used to assess the odds ratios of the AA-genotype in relation to LTPA, VO(2)max, REE, and GIT. RESULTS: The AA-genotype of FTO rs9939609 had higher REE in the age-adjusted model, but the association was eliminated when adjusting for FM and LBM. The AA-genotype was not associated with LTPA, VO(2)max, or GIT. This was not influenced by adjustment for age, FM, or LBM. The AA-genotype had increased FM, even with adjustment for age, LBM, REE, GIT, VO(2)max, and LTPA. Results were similar for FTO rs8050136 and rs7193144. CONCLUSIONS: Homozygous carriers of the A-allele of rs9939609 FTO do not have lower REE, GIT, VO(2)max, or LTPA but higher FM, irrespective of LBM, REE, GIT, VO(2)max, and LTPA.