Human Molecular Genetics Advance Access published online on December 17, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn431
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Association of functionally significant Melanocortin-4 but not Melanocortin-3 receptor mutations with severe adult obesity in a large North-American case control study
1 Diabetes Center, University of California San Francisco, San Francisco, California 94143, USA 2 Cardiovascular Research Institute, University of California San Francisco, San Francisco, California 94143, USA 3 Department of Medicine, University of California San Francisco, San Francisco, California 94143, USA 4 Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California 94143, USA 5 Department of Physiological Nursing, University of California San Francisco, San Francisco, California 94143, USA 6 Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA 7 Columbia University Center for Computational Biology and Bioinformatics (C2B2), New York, New York 10032, USA 8 U.S. Department of Energy Joint Genome Institute, Walnut Creek, and Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA 9 Division of Cardiology, University of Ottawa Heart Institute, Ottawa, K1Y 4W7, Canada 10 Department of Biopharmaceutical Sciences and Institute for Human Genetics, University of California San Francisco, San Francisco, California 94143, USA
* To whom correspondence should be addressed at: Diabetes Center, 513 Parnassus Ave, HSW 1113, University of California-San Francisco, San Francisco, CA 94143. Tel: +1 415 514 0530; Fax: +1 415 564 5813; Email: vaisse{at}diabetes.ucsf.edu
Received September 11, 2008; Revised December 12, 2008; Accepted December 12, 2008
Functionally significant heterozygous mutations in the Melanocortin-4 receptor (MC4R) have been implicated in 2.5% of early-onset obesity cases in European cohorts. The role of mutations in this gene in severely obese adults, particularly in smaller North American patient cohorts, has been less convincing. More recently, it has been proposed that mutations in a phylogenetically and physiologically related receptor, the Melanocortin-3 receptor (MC3R), could also be a cause of severe human obesity. The objectives of this study were to determine if mutations impairing the function of MC4R or MC3R were associated with severe obesity in North American adults. We studied MC4R and MC3R mutations detected in a total of 1821 adults (889 severely obese and 932 lean controls) from two cohorts. We systematically and comparatively evaluated the functional consequences of all mutations found in both MC4R and MC3R. The total prevalence of rare MC4R variants in severely obese North American adults was 2.25% (CI95% of 1.44–3.47) compared to 0.64% (CI95% of 0.26–1.43) in lean controls (p < 0.005). After classification of functional consequence, the prevalence of MC4R mutations with functional alterations was significantly greater as compared to controls (p < 0.005). In contrast, the prevalence of rare MC3R variants was not significantly increased in severely obese adults (0.67% (CI95% of 0.27-1.50) vs. 0.32% (CI95% of 0.06-0.99)) (p = 0.332). Our results confirm that mutations in MC4R are a significant cause of severe obesity, extending this finding to North American adults. However, our data suggest that MC3R mutations are not associated with severe obesity in this population.
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