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Mutation Screening of the Urocortin Gene: Identification of New Single Nucleotide Polymorphisms and Association Studies with Obesity in French Caucasians

Institute of Biology, Centre National de la Recherche Scientifique 8090 and University Hospital, Pasteur Institute of Lille (J.D., F.V., E.D., A.A., C.D., K.C., J.W., P.B., P.F.), F-59019 Lille, France; Department of Internal Medicine, University Hospital (A.A., G.W.), 1010 Lausanne, Switzerland; Nutrition Department, Hôtel Dieu (B.G.-G., K.C.), 75181 Paris, France; Pediatric Endocrinology Department, Jeanne de Flandre Hospital (J.W.), 59037 Lille, France; Barts and The London Genome Center, Queen Mary’s College, University of London (P.F.), London EC1 M6BQ, United Kingdom

Address all correspondence and requests for reprints to: Prof. P. Froguel, Centre National de la Recherche Scientifique 8090, Institut Pasteur de Lille, 1 rue Calmette, F-59019 Lille Cedex, France. E-mail: froguel{at}mail-good.pasteur-lille.fr

Abstract

A linkage between obesity-related phenotypes and the 2p21–23 locus has been reported previously. The urocortin (UCN) gene resides at this interval, and its protein decreases appetite behavior, suggesting that UCN may be a candidate gene for susceptibility to obesity. We localized the UCN gene by radiation hybrid mapping, and the surrounding markers were genotyped in a collection of French families. Evidence for linkage was shown between the marker D2S165 and leptin levels (LOD score, 1.34; P = 0.006) and between D2S2247 and the z-score of body mass index (LOD score, 1.829; P = 0.0019). The gene was screened for SNPs in 96 obese patients. Four new variants were established. Two single nucleotide polymorphisms were located in the promoter (-535 AG, -286 GA), one in intron 1 (+31 CG), and one in the 3'-untranslated region (+34 CT). Association studies in cohorts of 722 unrelated obese and 381 control subjects and transmission disequilibrium tests, performed for the two frequent promoter polymorphisms, in 120 families (894 individuals) showed that no association was present between these variants and obesity, obesity-related phenotypes, and diabetes. Thus, our analyses of the genetic variations of the UCN gene suggest that, at least in French Caucasians, they do not represent a major cause of obesity.

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