Mutational analysis of the proopiomelanocortin gene in Caucasians with early onset obesity

OBJECTIVE: Mutations in the human gene encoding the polyhormone peptide pro opiomelanocortin (POMC) are associated with obesity in rare cases and the g ene co-localizes with a reported quantitative trait loci (QTL) for variatio ns in circulating leptin levels and fat mass on human chromosome 2q21. In t his study we have used polymerase chain reaction (PCR) and single strand co nformation 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 codin g region of the POMC gene and 500 bp of the putative promoter region, by si ngle strand conformational analysis and sequencing, in 56 subjects with juv enile onset obesity (body mass index (BMI) greater than or equal to 31kg/m( 2) at the draft board examination). The prevalence of two polymorphisms wer e further studied in 156 obese and 205 control subjects, and in a populatio n 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(c odon6)c-->t Cys/Cys, No7726(codon116)c-->t Leu/Leu) of which one was preval ent (No8246(3'UTR)c-->t) and one variant changed an amino acid (No8086(codo n236)g-->c Arg/Gln). The amino acid substitution was only seen in one subje ct. Comparing the prevalence of the frequent No8246 silent polymorphism, in an association study comprising 156 subjects with juvenile onset obesity a nd 205 randomly sampled control subjects (mean BMI 23.5 +/- 4.7 kg/m(2)), d id not show any relationship to obesity. Also, comparing the prevalence of a known 9bp insertion/deletion variant in the coding region of the gene bet ween obese and lean, showed no association to obesity. Furthermore, analyzi ng a population based cohort of 380 young healthy Caucasians for the preval ent 3'UTR polymorphism as well as the 9bp insertion/deletion variant did no t 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 reg ion anti the putative promoter of the POMC gene are a major cause of juveni le onset human obesity.