Carcinogenesis Advance Access first published online on March 28, 2008
This version published online on April 11, 2008
Carcinogenesis, 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)
1 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
2 International Agency for Research on Cancer (IARC), Lyon, France
3 Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark
4 Department of Clinical Epidemiology, Aarhus University Hospital, Aalborg, Denmark
5 Inserm (Institut National de la Santé et de la Recherche Médicale), ERI 20, EA 4045, and Institut Gustave Roussy, Villejuif, France
6 Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
7 Department of Hygiene and Epidemiology, University of Athens Medical School, Athens, Greece
8 Department of Epidemiology, Harvard School of Public Health, USA and Hellenic Health Foundation, Greece
9 Molecular and Nutritional Epidemiology Unit, CSPO-Scientific Institute of Tuscany, Florence, Italy
10 Nutritional Epidemiology Unit, National Cancer Institute, Milan, Italy
11 Cancer Registry Azienda Ospedaliera Civile-M.P. Arezzo, Ragusa, Italy
12 Department of Epidemiology and Public Health, Imperial College, London, United Kingdom
13 Public Health and Health Planning Directorate, Asturias, Spain
14 Laboratori de Recerca Translacional and Department of Epidemiology, Catalan Institute of Oncology, Barcelona (ICO-IDIBELL), Spain
15 Andalusian School of Public Health and CIBER Epidemilogía y Salud Pública, Granada, Spain
16 Department of Public Health of Guipuzkoa, San Sebastian, Spain
17 Epidemiology Department, Murcia Health Council, CIBER en Epidemiología y Salud Pública (CIBERESP), Murcia, Spain
18 Public Health Institute of Navarra, CIBER Epidemiología y Salud Pública (CIBERESP), Pamplona, Spain
19 Center for Nutrition and Health, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
20 Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, the Netherlands
21 Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden
22 Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
23 MRC Dunn Human Nutrition Unit, Cambridge, UK & MRC Centre for Nutritional Epidemiology in Cancer Prevention and Survival, Department of Public Health and Primary Care, University of Cambridge, United Kingdom
24 Department of Public Health and Primary Care, University of Cambridge, United Kingdom
25 Cancer Research UK, Epidemiology Unit, University of Oxford, Oxford, United Kingdom
* Correspondence to: Prof. Rudolf Kaaks, Division of Cancer Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany, Tel: +49-(0)6221-422219, Fax: +49-(0)6221-422203, E-mail: 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 (EPIC), 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 (IGFBP-3) and breast cancer risk.
Pairwise 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 (OR: 1.2; 95%CI: 1.0-1.4; P = 0.02). The GHRL SNP 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 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 body-mass-index. 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.
Key Words: anthropometry • breast cancer • ghrelin • GHRL • GHSR • IGF-I • IGFBP-3 • obesity • single nucleotide polymorphisms
Received January 9, 2008; revised March 3, 2008; accepted March 19, 2008.