A missense mutation in the human melanocortin-4 receptor gene in relation to abdominal obesity and salivary cortisol

Aims/hypothesis. The melanocortin-4 receptor (MC4-R) regulates food intake and possibly energy expenditure, and the inactivation of the MC4-R by gene targeting results in obesity, a phenotype strongly associated with Type II (non-insulin-dependent) diabetes mellitus. In our study, we addressed the h ypothesis that a G --> A substitution at codon 103 (Val103Ile) of the MC4R gene influences abdominal obesity, insulin, glucose, and lipid metabolism a s well as circulating hormones, including salivary cortisol. Methods. We genotyped the missense variant at codon 103 of the MC4R gene in 284 unrelated Swedish men born in 1944 by using polymerase chain reaction amplification followed by digestion with the restriction enzyme HincII. Results. The frequency of allele G was 0.97 and 0.03 for allele A. The obse rved genotype frequencies were 95% and 5% for G/G and G/A, respectively. Th e heterozygotes had lower waist-to-hip ratio (p = 0.023) and trends for low er body mass index (p = 0.054) and abdominal sagittal diameter (p = 0.095) compared to G/G homozygotes. Moreover, G/A subjects had borderline lower se rum leptin concentrations (p = 0.087) and total cholesterol (p = 0.082). Th e heterozygotes had also, in comparison to G/G subjects, significantly (p < 0.01) higher mean cortisol concentrations in the morning (21.4 vs 14.6 nmo l/l), at 11:45 h (11.6 vs 7.0 nmol/l), 30 min after a standardized lunch (1 5.3 vs 8.0 nmol/l) and finally, 60 min after lunch (10.8 vs 6.7 nmol/l). Conclusion/interpretation. These findings suggest that the missense mutatio n in the MC4R gene could contribute to the variability in body mass, abdomi nal fat distribution and leptin concentrations in the general population. M oreover, the G/A mutation exhibits evidence of associations with diurnal co rtisol levels.