Linkage and association studies between the proopiomelanocortin (POMC) gene and obesity in Caucasian families

Aims/hypothesis. The region 2p21-23, containing the proopiomelanocortin gen e (POMC), was reported to be linked to leptin concentrations in Mexican-Ame rican, French and African-American cohorts. A polyhormone peptide, POMC is expressed in brain, gut, placenta and pancreas. The POMC mutations are resp onsible for rare cases of early-onset obesity. Thus we examined the contrib ution of the POMC locus to obesity in French families. Methods. Single and multipoint linkage studies were done between obesity, o besity associated-phenotypes (leptin values and z-score of the body mass in dex) and three newly mapped markers surrounding POMC in 264 affected sib-pa irs from French obese families. Mutation screening of the exons and intron/ exon junctions of the POMC gene was realised by direct sequencing. Associa tion studies were done in 379 unrelated obese patients and 370 non-obese no n-diabetic subjects. Results. Linkage analysis confirmed the trend towards linkage between polym orphic markers around POMC and variations of leptin concentrations and z-sc ore (maximum lod score at D2S2337 = 2.03). Mutation screening of the POMC g ene in the French Caucasian cohort identified two previously reported polym orphisms. None of these variants was associated with obesity, diabetes or s erum leptin and lipid concentrations. Conclusion/interpretation. Our results indicate that mutations in the POMC gene do not contribute to the variance of obesity associated phenotypes, at least in French Caucasians. Given the replicated evidence of linkage betwe en leptin values and the chromosome 2p21-23 region in different populations , it is likely that functional variant(s) in the POMC regulating sequences or in an unknown gene in this region explains this linkage.