J. Lipid Res.
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A more recent version of this article appeared on April 1, 2006

Papers In Press, published online ahead of print January 25, 2006
J. Lipid Res., doi:10.1194/jlr.M500338-JLR200
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Submitted on August 2, 2005
Revised on January 6, 2006
Accepted on January 24, 2006

Sequence variants in the melatonin-related receptor (GPR50) gene associate with circulating triglyceride and HDL levels

Sumit Bhattacharyya, Jian’an Luan, Benjamin Challis, Julia Keogh, Carl Montague, John Brennand, John Morten, Sarah Lowenbeim, Suzanne Jenkins, Sadaf Farooqi, Nicholas J. Wareham, and Stephen O’Rahilly

EBI, Cambridge, Cambridgeshire CB10 1SD

Corresponding Author: sumit{at}ebi.ac.uk

The gene encoding the melatonin-related receptor (GPR50) is highly expressed within hypothalamic nuclei concerned with the control of body weight and metabolism. We screened GPR50 for mutations in a cohort of 95 subjects with severe early onset obesity. We identified an insertion of 4 amino acid residues (TTGH) at position 501, two common coding (T528A and V602I) and 1 non-coding polymorphism (C-16X2GPR50T). These variants were found at similar frequencies in unaffected control individuals. To establish whether variation in GPR50 associated with intermediate obesity phenotypes, the four SNPs were typed in 500 UK Caucasian subjects. While no association with body mass index was seen, carriers of two copies of the mutant allele at C-16X2GPR50T, Ins501Del and A1582G (T528A) had significantly higher fasting circulating triglyceride levels than their wild-type counterparts (p<0.05). In a separate set of 585 subjects the associations were replicated with statistically significant effects of similar magnitude and direction. Taken together the association of C-16X2GPR50T, with fasting triglyceride was highly significant (p<0.001) In addition, a significant association between C-16X2GPR50T and circulating HDL levels was observed in the combined population, with C-16X2GPR50T carriers having significantly lower circulating HDL-cholesterol levels (1.39 mM) than wild-type subjects (1.47 mM) (p<0.01). These findings suggest a previously unexpected role for this orphan receptor in the regulation of lipid metabolism that warrants further investigation.


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