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Examining the Candidacy of Ghrelin as a Gene Responsible for Variation in Adult Stature in a United Kingdom Population with Type 2 Diabetes

Department of Endocrinology (M.G., E.A.G., A.B.G., M.K.), Genome Centre (C.M., B.K.), William Harvey Research Institute and Centre of Diabetes and Metabolic Medicine, Institute of Cell and Molecular Sciences (R.A., G.A.H.), Barts and the London Queen Mary’s School of Medicine and Dentistry, University of London, London, E1 2AD, United Kingdom; Wellcome Trust Centre for Human Genetics (S.W., M.I.M.), University of Oxford, Oxford, OX3 7BN, United Kingdom; Centre National de la Recherche Scientifique 8900 (C.L., P.F.), Institute of Biology, Pasteur Institute, 59000 Lille, France; Institute of Clinical and Biomedical Research (A.T.H.), Peninsula Medical School, Exeter, EX2 4NT, United Kingdom; Department of Medicine (M.W.), School of Medicine, University of Newcastle, Newcastle-upon-Tyne, NE1 7RU, United Kingdom; Departments of Medicine and Clinical Biochemistry (S.O.), Addenbrooke’s Hospital, University of Cambridge, Cambridge, CB2 2QQ, United Kingdom; Imperial College Genome Centre and Genomic Medicine (P.F.), Hammersmith Hospital, Imperial College London, London, W12 0NN, United Kingdom; and Oxford Centre for Diabetes, Endocrinology and Metabolism (M.I.M.), Churchill Hospital, Oxford, OX3 7LJ, United Kingdom

Address all correspondence and requests for reprints to: Márta Korbonits, M.D., Ph.D., Reader in Endocrine Research, Department of Endocrinology, Room 114C, John Vane Science Centre, Barts and the London Medical School, Charterhouse Square, London EC1M 6BQ, United Kingdom. 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 GH release and located on 3p26, we hypothesized that variation within its gene (GHRL) 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 five common single nucleotide polymorphisms (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 an LOD score of 2.58 (P = 0.0003) between D3S1297 and D3S1304. Five common (frequency of 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.