Mutational analysis of the proopiomelanocortin gene in Caucasians with early onset obesity.
OBJECTIVE: Mutations in the human gene encoding the polyhormone peptide proopiomelanocortin (POMC) are associated with obesity in rare cases and the gene co-localizes with a reported quantitative trait loci (QTL) for variations in circulating leptin levels and fat mass on human chromosome 2p21. In this study we have used polymerase chain reaction (PCR) and single strand conformation polymorphism (SSCP) analysis, to test whether variations in the human POMC gene are associated with human obesity. DESIGN AND SUBJECTS: Primary mutational analysis was performed on the coding region of the POMC gene and 500 bp of the putative promoter region, by single strand conformational analysis and sequencing, in 56 subjects with juvenile onset obesity (body mass index (BMI) > or = 31 kg/m2 at the draft board examination). The prevalence of two polymorphisms were further studied in 156 obese and 205 control subjects, and in a population based cohort of 380 extensively characterized young healthy subjects. RESULTS: We have identified a total of six gene variants, five were silent nucleotide substitutions (No51(promoter) g-->c, No670(5'UTR)g-->a, No4512(codon6)c-->t Cys/Cys, No7726(codon116)c-->t Leu/Leu) of which one was prevalent (No8246(3'UTR)c-->t) and one variant changed an amino acid (No8086(codon236)g-->c Arg/Gln). The amino acid substitution was only seen in one subject. Comparing the prevalence of the frequent No8246 silent polymorphism, in an association study comprising 156 subjects with juvenile onset obesity and 205 randomly sampled control subjects (mean BMI 23.5+/-4.7 kg/m2), did not show any relationship to obesity. Also, comparing the prevalence of a known 9bp insertion/deletion variant in the coding region of the gene between obese and lean, showed no association to obesity. Furthermore, analyzing a population based cohort of 380 young healthy Caucasians for the prevalent 3'UTR polymorphism as well as the 9 bp insertion/deletion variant did not show any association to deviations in body fat contents or fasting serum leptin concentrations. CONCLUSION: In conclusion, it is unlikely that variations in the coding region and the putative promoter of the POMC gene are a major cause of juvenile onset human obesity.