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Journal of Lipid Research, Vol. 47, 761-766, April 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Sequence variants in the melatonin-related receptor gene (GPR50) 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^**, I. Sadaf Farooqi^*,, Nicholas J. Wareham and Stephen O'Rahilly^1,*,

^* Department of Medicine, University of Cambridge, Cambridge, UK
Department of Clinical Biochemistry, University of Cambridge, Cambridge, UK
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
^** Cardiovascular & Gastrointestinal Department Discovery, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, UK

Published, JLR Papers in Press, January 25, 2006.

¹ To whom correspondence should be addressed. e-mail: so104{at}medschl.cam.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 an obese cohort and identified an insertion of four amino acid residues (TTGH) at position 501, two common coding polymorphisms (T528A and V602I), and one noncoding polymorphism (C-16X2GPR50T). Single-nucleotide polymorphisms were then typed in 500 English Caucasian subjects, and associations were sought to intermediate obesity phenotypes. Although no association was seen with body mass index, carriers of two copies of the mutant allele at C-16X2GPR50T, Ins501Del, and A1582G had significantly higher fasting circulating triglyceride levels (P < 0.05). In a separate set of 585 subjects, the associations were replicated, with statistically significant effects of similar magnitude and direction. The association of C-16X2GPR50T with fasting triglycerides 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.

Supplementary key words bipolar • metabolic • neuronal

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