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This version published online on March 27, 2007
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-2657
A more recent version of this article appeared on June 1, 2007
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Submitted on December 4, 2006
Accepted on March 21, 2007

Examining the candidacy of ghrelin as a gene responsible for variation in adult stature in a UK population with type 2 diabetes

Maria Gueorguiev, Steven Wiltshire, Edwin A. Garcia, Charles Mein, Cecile Lecoeur, Brigitte Kristen, Rebecca Allotey, Andrew T. Hattersley, Mark Walker, Stephen O'Rahilly, Philippe Froguel, Ashley B. Grossman, Mark I. McCarthy, Graham A. Hitman, and Márta Korbonits*

Department of Endocrinology, William Harvey Research Institute, Barts and the London Queen Mary's School of Medicine and Dentistry, University of London, London EC1M 6BQ, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; Genome Centre, Barts and the London Queen Mary's School of Medicine and Dentistry, University of London, London EC1M 6BQ, UK; Centre National de la Recherche Scientifique 8900-Institute of Biology, Pasteur Institute, 59000 Lille, France; Centre of Diabetes and Metabolic Medicine, Institute of Cell and Molecular Sciences, Barts and the London Queen Mary's School of Medicine and Dentistry, University of London, London E1 2AT, UK; Institute of Clinical and Biomedical Research, Peninsula Medical School, Exeter; Department of Medicine, School of Medicine, Newcastle upon-Tyne, UK; Departments of Medicine and Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge; Imperial College Genome Centre and Genomic Medicine, Hammersmith Hospital, Imperial College London, London W12 0NN, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM) Churchill Hospital, Old Road Headington, Oxford, OX3 7LJ, UK

* To whom correspondence should be addressed. E-mail: m.korbonits{at}qmul.ac.uk.

Context: Recently, a quantitative trait locus for stature was reported on chromosome 3p26 in patients with type 2 diabetes.

Objective: Given that ghrelin is a peptide involved in growth hormone release and located on 3p26, we hypothesized that variation within its gene (GHRL) it may be responsible for the quantitative trait locus on 3p26.

Design: The evidence for linkage around GHRL was refined with the genotyping of an additional four microsatellites (D3S4545, D3S1537, D3S1597 and D3S3611), giving a total of 27 markers, followed by multipoint variance components linkage analysis. Probands from the linkage families were typed for 5 common SNPs within GHRL and tested for association with adult stature using haplotype trend regression.

Results: The maximum multipoint evidence for linkage between adult stature and the 27 microsatellites yielded a LOD score of 2.58 (P=0.0003) between D3S1297 and D3S1304. Five common (frequency≥5%) SNPs were typed in the probands - two promoter SNPs (rs27647 and rs26802), two exonic (rs696217 and rs4684677) and one intronic (rs35683) - capturing 80% of the total common variation in GHRL. No association was found between any SNP (or haplotypes thereof) and adult stature.

Conclusion: Common genetic variation within GHRL is not responsible for variation in adult stature in this population.


Key words: ghrelin • GHRL • Quantitative Trait Loci • linkage analysis • association studies







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