Association of melanin-concentrating hormone receptor 1 5' polymorphism with early-onset extreme obesity.
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.
Bell
Christopher G
CG
Section of Genomic Medicine, Faculty of Medicine, Imperial College, Hammersmith Hospital, London W12 0NN, UK.
Meyre
David
D
Samson
Chantal
C
Boyle
Cliona
C
Lecoeur
Cécile
C
Tauber
Maïte
M
Jouret
Béatrice
B
Jaquet
Delphine
D
Levy-Marchal
Claire
C
Charles
Marie Aline
MA
Weill
Jacques
J
Gibson
Fernando
F
Mein
Charles A
CA
Froguel
Philippe
P
Walley
Andrew J
AJ
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*
C103263:MCHR1 protein, human; D017481:Receptors, Somatostatin