Common genetic variation in and near the melanocortin 4 receptor gene (MC4R) is associated with body mass index in American Indian adults and children.

Six rare functional coding mutations were previously identified in melanocortin 4 receptor (MC4R) in 6,760 American Indians. Individuals heterozygous for one of these mutations become obese while young. We now investigate whether common non-coding variation near MC4R also contributes to obesity. Fifty-six tag single-nucleotide polymorphisms (SNPs) were genotyped in 3,229 full-heritage Pima Indians, and nine of these SNPs which showed evidence for association were genotyped in additional 3,852 mixed-heritage American Indians. Associations of SNPs with maximum body mass index (BMI) in adulthood (n = 5,918), BMI z score in childhood (n = 5,350), percent body fat (n = 864), energy expenditure (n = 358) and ad libitum food intake (n = 178) were assessed. Conditional analyses demonstrated that SNPs, rs74861148 and rs483125, were independently associated with BMI in adulthood (ß = 0.68 kg/m(2) per risk allele, p = 5 × 10(-5); ß = 0.58 kg/m(2), p = 0.002, respectively) and BMI z score in childhood (ß = 0.05, p = 0.02; ß = 0.07, p = 0.01, respectively). One haplotype (frequency = 0.35) of the G allele at rs74861148 and the A allele at rs483125 provided the strongest evidence for association with adult BMI (ß = 0.89 kg/m(2), p = 5.5 × 10(-7)), and was also associated with childhood BMI z score (ß = 0.08, p = 0.001). In addition, a promoter SNP rs11872992 was nominally associated with adult BMI (ß = 0.61 kg/m(2), p = 0.05) and childhood BMI z score (ß = 0.11, p = 0.01), where the risk allele also modestly decreased transcription in vitro by 12 % (p = 0.005). This risk allele was further associated with increased percent body fat (ß = 2.2 %, p = 0.002), increased food intake (ß = 676 kcal/day, p = 0.007) and decreased energy expenditure (ß = -53.4 kcal/day, p = 0.054). Common and rare variation in MC4R contributes to obesity in American Indians.

Common genetic variation in the glucokinase gene (GCK) is associated with type 2 diabetes and rates of carbohydrate oxidation and energy expenditure.

AIMS/HYPOTHESIS: Glucokinase (GCK) plays a role in glucose metabolism and glucose-stimulated insulin secretion. Rare mutations in GCK cause MODY. We investigated whether common variation (minor allele frequency ≥0.01) in GCK is associated with metabolic traits and type 2 diabetes. METHODS: Four exonic single-nucleotide polymorphisms (SNPs) and three SNPs predicted to cause loss of promoter function were identified in whole-genome sequence data from 234 Pima Indians. These seven tag SNPs and rs4607517, a type 2 diabetes variant established in other studies, were analysed in 415 full-heritage non-diabetic Pima Indians characterised for metabolic traits, and 7,667 American Indians who had data on type 2 diabetes and BMI. RESULTS: A novel 3' untranslated region (3'UTR) SNP, chr7:44184184-G/A, was associated with the rate of carbohydrate oxidation post-absorptively (ß = 0.22 mg [kg estimated metabolic body size (EMBS)](-1) min(-1), p = 0.005) and during a hyperinsulinaemic-euglycaemic clamp (ß = 0.24 mg [kg EMBS](-1) min(-1), p = 0.0002), the rate of carbohydrate oxidation in a respiratory chamber (ß = 311 kJ/day, p = 0.03) and 24 h energy expenditure, which was attributable to the thermic effect of food (ß = 520 kJ/day, p = 3.39 × 10(-6)). This 3'UTR SNP was also associated with diabetes (OR 1.36, 95% CI 1.11, 1.65, p = 0.002), where the A allele (allele frequency 0.05) was associated with a lower rate of carbohydrate oxidation, lower 24 h energy expenditure and higher risk for diabetes. In a Cox proportional hazards model, a rate of insulin-stimulated carbohydrate oxidation lower than the mean rate at baseline predicted a higher risk for developing diabetes than for those above the mean (hazard rate ratio 2.2, 95% CI 1.3, 3.6, p = 0.002). CONCLUSIONS/INTERPRETATION: Common variation in GCK influences the rate of carbohydrate oxidation, 24 h energy expenditure and diabetes risk in Pima Indians.