title: Association of melanin-concentrating hormone receptor 1 5' polymorphism with early-onset extreme obesity.
abstract: Murine models have been highly effective in identifying the monogenic forms of human obesity discovered to date. Melanin-concentrating hormone receptor 1 (MCHR1) has been shown to be significant in the downstream orexigenic activity of the leptin-melanocortin pathway by such models. In this study, the human MCHR1 gene was extensively characterized by sequencing 3.5 kb of coding, untranslated and intronic regions plus 1 kb of putative promoter region in 180 morbidly obese adults and 87 morbidly obese children, a total of >2.4 Mb of sequencing. Thirty-nine single nucleotide polymorphisms (SNPs) were found, seven of which encode an amino acid change. One mutation, R248Q, appeared to cosegregate with the obesity trait in one pedigree but was also found to be a rare polymorphism in control samples. To investigate the possible polygenic role of MCHR1, the six common SNPs (minor allele frequency >5%) found in the sequenced regions were then screened in 557 morbidly obese adults, 552 obese children, and 1,195 nonobese nondiabetic control subjects. The plausible promoter SNP, rs133068, was found to be associated with protection against obesity in obese children only (allele frequency P = 0.006 and genotype frequency P = 0.004). Most significant results were found when using a dominant model (P = 0.001, odds ratio 0.695 [95% CI 0.560-0.863]). However, similar associations were found when both adults and children were analyzed together (P = 0.006, 0.783 [0.658-0.930]), suggesting that severe forms of obesity with early onset may be associated with SNPs in MCHR1.
authors.affiliation: Section of Genomic Medicine, Faculty of Medicine, Imperial College, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Bell
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.forename: Chantal
authors.initials: C
authors.lastname: Samson
authors.forename: Cliona
authors.initials: C
authors.lastname: Boyle
authors.forename: Cécile
authors.initials: C
authors.lastname: Lecoeur
authors.forename: Maïte
authors.initials: M
authors.lastname: Tauber
authors.forename: Béatrice
authors.initials: B
authors.lastname: Jouret
authors.forename: Delphine
authors.initials: D
authors.lastname: Jaquet
authors.forename: Claire
authors.initials: C
authors.lastname: Levy-Marchal
authors.forename: Marie Aline
authors.initials: MA
authors.lastname: Charles
authors.forename: Jacques
authors.initials: J
authors.lastname: Weill
authors.forename: Fernando
authors.initials: F
authors.lastname: Gibson
authors.forename: Charles A
authors.initials: CA
authors.lastname: Mein
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Walley
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D015992:Body Mass Index; D002462:Cell Membrane / Q000737:chemistry; D002648:Child; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009767:Obesity, Morbid / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017481:Receptors, Somatostatin / Q000737:chemistry / Q000235:genetics*
chemical_list: C103263:MCHR1 protein, human; D017481:Receptors, Somatostatin