Carcinogenesis Advance Access originally published online on March 28, 2008
Carcinogenesis 2008 29(7):1360-1366; doi:10.1093/carcin/bgn083
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Polymorphisms of genes coding for ghrelin and its receptor in relation to anthropometry, circulating levels of IGF-I and IGFBP-3, and breast cancer risk: a case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
1 Genetic Epidemiology Group
2 Epidemiology Methods and Support Group, International Agency for Research on Cancer, Lyon 69372, France
3 Department of Diet, Cancer and Health, Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen 2100, Denmark
4 Department of Clinical Epidemiology, Aarhus University Hospital, Aalborg Aarhus 8000, Denmark
5 Department of Epidemiology and Public Health, Institut National de la Santé et de la Recherche Médicale, ERI 20, EA 4045 and Institut Gustave Roussy, Villejuif 94805, France
6 Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal 14558, Germany
7 Department of Hygiene and Epidemiology, University of Athens Medical School, Athens 11527, Greece
8 Department of Epidemiology, Harvard School of Public Health, Boston MA 02115, USA
9 Hellenic Health Foundation, Athens 11527, Greece
10 Molecular and Nutritional Epidemiology Unit, Center for Cancer Research and Prevention-Scientific Institute of Tuscany, Florence 50139, Italy
11 Nutritional Epidemiology Unit, National Cancer Institute, Milan 20133, Italy
12 Cancer Registry, Azienda Ospedaliera Civile M.P. Arezzo, Ragusa 97100, Italy
13 Department of Epidemiology and Public Health, Imperial College, London SW7, UK
14 Public Health and Health Planning Directorate, Asturias Oviedo 33001, Spain
15 Laboratori de Recerca Translacional, Department of Epidemiology, Catalan Institute of Oncology, Barcelona (Institut d'Investigatio Biomedica de Bellvitge), L'Hospitalet de Llobregat, Barcelona 08907, Spain
16 Andalusian School of Public Health, CIBER Epidemilogía y Salud Pública, Granada 18011, Spain
17 Department of Public Health of Guipuzkoa, San Sebastian, Donostia-San Sebastian 20013, Spain
18 Department of Epidemiology, Murcia Health Council, CIBER en Epidemiología y Salud Pública (CIBERESP), Murcia Granada 18011, Spain
19 Public Health Institute of Navarra, CIBERESP, Pamplona 31003, Spain
20 Center for Nutrition and Health, National Institute for Public Health and the Environment, Bilthoven 3720 BA, The Netherlands
21 Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht 3508 GA, The Netherlands
22 Department of Public Health and Clinical Medicine, Nutritional Research, Oncology, Umeå University, Umeå 90187, Sweden
23 Department of Radiation Sciences, Oncology, Umeå University, Umeå 90187, Sweden
24 MRC Dunn Human Nutrition Unit, Cambridge CB2 0XY, UK
25 MRC Centre for Nutritional Epidemiology in Cancer Prevention and Survival Department of Public Health and Primary Care, University of Cambridge CB1 8RN, UK
26 Department of Public Health and Primary Care, University of Cambridge CB1 8RN, UK
27 Cancer Research UK, Epidemiology Unit, University of Oxford, Oxford OX3 7XP, UK
* To whom correspondence should be addressed. Tel: +49 6221 422219; Fax: +49 6221 422203;Email: r.kaaks{at}dkfz.de
Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, has two major functions: the stimulation of the growth hormone production and the stimulation of food intake. Accumulating evidence also suggests a role of ghrelin in cancer development. We conducted a case–control study on 1359 breast cancer cases and 2389 matched controls, nested within the European Prospective Investigation into Cancer and Nutrition, to examine the association of common genetic variants in the genes coding for ghrelin (GHRL) and its receptor (GHSR) with anthropometric measures, circulating insulin growth factor I (IGF-I) and insulin-like growth factor-binding protein 3 and breast cancer risk. Pair-wise tagging was used to select the 15 polymorphisms that represent the majority of common genetic variants across the GHRL and GHSR genes. A significant increase in breast cancer risk was observed in carriers of the GHRL rs171407-G allele (odds ratio: 1.2; 95% confidence interval: 1.0–1.4; P = 0.02). The GHRL single-nucleotide polymorphism rs375577 was associated with a 5% increase in IGF-I levels (P = 0.01). A number of GHRL and GHSR polymorphisms were associated with body mass index (BMI) and height (P between <0.01 and 0.04). The false-positive report probability (FPRP) approach suggests that these results are noteworthy (FPRP < 0.20). The results presented here add to a growing body of evidence that GHRL variations are associated with BMI. Furthermore, we have observed evidence for association of GHRL polymorphisms with circulating IGF-I levels and with breast cancer risk. These associations, however, might also be due to chance findings and further large studies are needed to confirm our results.
Abbreviations: BMI, body mass index; EPIC, European Prospective Investigation into Cancer and Nutrition; FPRP, false-positive report probability; GH, growth hormone; GHSR, growth hormone secretagogue receptor; IGFBP-3, insulin-like growth factor-binding protein 3; IGF-I, insulin growth factor I; SNP, single-nucleotide polymorphism
Received January 9, 2008; revised March 3, 2008; accepted March 19, 2008.
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