Melanocortin-3-receptor gene variants in morbid obesity

Linkage and knock-out mice studies suggest that the melanocortin-3-receptor (MC3R) is a candidate gene for obesity.

To evaluate whether MC3R mutations underlie morbid obesity.

MC3R coding and 5(')-flanking regions were sequenced in 48 subjects and the detected variants genotyped in 252 morbidly obese (BMI>/=40 kg/m(2)) Finns. Gel shifts were used to examine whether a mutation in the putative promoter alters GATA-factor binding.

Three common MC3R variants were found: a 17C>A variant, changing Thr6-->Lys in 16%, a 241G>A variant changing Val81-->Ile in 15%, and a -239A>G substitution in the GATA binding site in 21% of the subjects. Four other variants were detected in the 5(') flanking region. Frequencies of the three common variants did not differ between obese and contol subjects. Among the obese, the 17C>A and 241G>A variants were coinherited and associated with increased insulin-glucose ratios (P<0.05) and leptin levels (P<0.05). GATA-4 bound efficiently to wild type oligonucleotide, but only weakly to the oligonucleotide with the -239A>G mutation.

MC3R gene variants are common and do not explain human morbid obesity. These variants associated with subtle changes in onset of weight gain, hyperleptinemia and insulin-glucose ratios. The -239A>G mutation abolishes binding of GATA-4 to the MC3R promoter region.