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Association of melanin-concentrating hormone receptor 1 5' polymorphism with early-onset extreme obesity.

Association of melanin-concentrating hormone receptor 1 5' polymorphism with early-onset extreme obesity.
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.
0012-1797
3049-3055
Bell, Christopher
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Meyre, David
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Samson, Chantal
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Boyle, Cliona
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Lecoeur, Cécile
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Tauber, Maïte
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Jouret, Béatrice
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Jaquet, Delphine
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Levy-Marchal, Claire
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Charles, Marie Aline
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Weill, Jacques
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Gibson, Fernando
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Mein, Charles A.
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Froguel, Philippe
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Walley, Andrew J.
354e9819-2ef2-44ac-81dc-8068aa354c74
Bell, Christopher
44982df7-0746-4cdb-bed1-0bdfe68f1a64
Meyre, David
023f567d-798c-41f0-a096-2028569a3976
Samson, Chantal
6c6af93b-5f91-4622-a29e-1cd16c37219a
Boyle, Cliona
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Lecoeur, Cécile
de08c41b-c24a-4ec3-82ef-c58a68a8ed34
Tauber, Maïte
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Jouret, Béatrice
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Jaquet, Delphine
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Levy-Marchal, Claire
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Charles, Marie Aline
de6a8f2e-075c-48d6-af11-ca6431616f56
Weill, Jacques
88b8cfe1-f76d-435f-a7a3-72cdb7d93c01
Gibson, Fernando
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Mein, Charles A.
c1cc43af-6c34-47a4-a959-5105593bcbde
Froguel, Philippe
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Walley, Andrew J.
354e9819-2ef2-44ac-81dc-8068aa354c74

Bell, Christopher, Meyre, David, Samson, Chantal, Boyle, Cliona, Lecoeur, Cécile, Tauber, Maïte, Jouret, Béatrice, Jaquet, Delphine, Levy-Marchal, Claire, Charles, Marie Aline, Weill, Jacques, Gibson, Fernando, Mein, Charles A., Froguel, Philippe and Walley, Andrew J. (2005) Association of melanin-concentrating hormone receptor 1 5' polymorphism with early-onset extreme obesity. Diabetes, 54 (10), 3049-3055. (doi:10.2337/diabetes.54.10.3049). (PMID:16186414)

Record type: Article

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.

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Accepted/In Press date: 1 June 2005
Published date: October 2005
Organisations: Human Development & Health, Centre for Biological Sciences, MRC Life-Course Epidemiology Unit

Identifiers

Local EPrints ID: 400998
URI: https://eprints.soton.ac.uk/id/eprint/400998
ISSN: 0012-1797
PURE UUID: bc000975-1037-4c2f-9ac6-1fcfd20bc142
ORCID for Christopher Bell: ORCID iD orcid.org/0000-0003-4601-1242

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Date deposited: 03 Oct 2016 14:02
Last modified: 11 Apr 2019 00:30

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