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Haplotype-Based Analysis of Common Variation in the Acetyl-CoA Carboxylase Gene and Breast Cancer Risk: A Case-Control Study Nested within the European Prospective Investigation into Cancer and Nutrition

¹ IARC; ² Hospices Civils de Lyon-Centre Léon Bérard, Lyon, France; ³ Department of Clinical Epidemiology, Aalborg Hospital, Aarhus University Hospital, Aarhus, Denmark; ⁴ Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark; ⁵ Equipe Nutrition, Hormones et Cancer, Institut Gustave Roussy, Villejuif, France; ⁶ Centre National de la Recherche Scientifique-FRE 2939, Institut Gustave Roussy, Villejuif, France; ⁷ German Cancer Research Centre, Clinical Epidemiology, Nutritional Epidemiology, Heidelberg, Germany; ⁸ Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany; ⁹ Department of Hygiene and Epidemiology, School of Medicine, University of Athens, Athens, Greece; ¹⁰ University of Cambridge School of Clinical Medicine; ¹¹ Medical Research Council Dunn Human Nutrition Unit and Medical Research Council Centre for Nutritional Epidemiology in Cancer Prevention and Survival, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; ¹² Epidemiology Unit, Cancer Research UK, University of Oxford, Oxford, United Kingdom; ¹³ Molecular and Nutritional Epidemiology Unit, CSPO-Scientific Institute of Tuscany, Florence, Italy; ¹⁴ Dipartimento di Medicina Clinica e Sperimentale, Universita' Federico II, Naples, Italy; ¹⁵ National Cancer Institute, Milan, Italy; ¹⁶ Cancer Registry, Azienda Ospedaliera "Civile M.P.Arezzo," Ragusa, Italy; ¹⁷ Department of Biomedical Science and Human Oncology CPO-Piemonte, Turin, Italy; ¹⁸ Centre for Nutrition and Health, National Institute of Public Health and the Environment, Bilthoven, the Netherlands; ¹⁹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; ²⁰ Institute of Community Medicine, University of Tromso, Tromso, Norway; ²¹ Unit of Epidemiology, Catalan Institute of Oncology, Barcelona, Spain; ²² Public Health and Health Planning Directorate, Asturias, Spain; ²³ Public Health Division of Gipuzkoa, Health Department of the Basque Country, Donostia-San Sebastian, Spain; ²⁴ Andalusian School of Public Health, Granada, Spain; ²⁵ Conserejía de Sanidad, Murcia, Spain; ²⁶ Public Health Institute of Navarra, Pamplona, Spain; ²⁷ Department of Public Health and Clinical Medicine, University of Umeå; ²⁸ Department of Radiation Sciences, Oncology, Norrland University Hospital, Umeå, Sweden; Departments of ²⁹ Clinical Sciences and ³⁰ Surgery, Malmö University Hospital, Malmö, Sweden; and ³¹ Department of Epidemiology and Public Health, Faculty of Medicine, Imperial College London, St. Mary's Campus, London, United Kingdom

Requests for reprints: Rudolf Kaaks, Division of Cancer Epidemiology, German National Cancer Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. Phone: 49-6221-42-23-85. E-mail: r.kaaks{at}dkfz-heidelberg.de

A key fatty acid synthesis enzyme, acetyl-CoA carboxylase (ACC-), has been shown to be highly expressed in human breast cancer and other tumor types and also to specifically interact with the protein coded by one of two major breast cancer susceptibility genes BRCA1. We used a comprehensive haplotype analysis to examine the contribution of the ACC- common genetic variation (allele frequency >5%) to breast cancer in a case-control study (1,588 cases/2,600 controls) nested within the European Prospective Investigation into Cancer and Nutrition. We identified 21 haplotype-tagging polymorphisms efficiently capturing common variation within 325 kb of ACC- and surrounding sequences using genotype data from the HapMap project and our resequencing data. We found an effect on overall risk of breast cancer in homozygous carriers of one common haplotype [odds ratio (OR), 1.74; 95% confidence interval (95% CI), 1.03-2.94]. When the data were subdivided by menopausal status, we found statistical evidence of heterogeneity for two other common haplotypes (P value for heterogeneity = 0.016 and 0.045). In premenopausal women, the carriers of these haplotypes, compared with noncarriers, had an altered risk of breast cancer (OR, 0.70; 95% CI, 0.53-0.92 and OR, 1.35; 95% CI, 1.04-1.76). These findings were not significant after adjustment for multiple testing and therefore should be considered as preliminary and evaluated in larger independent studies. However, they suggest a possible role of the ACC- common sequence variants in susceptibility to breast cancer and encourage studies of other genes involved in fatty acid synthesis. (Cancer Epidemiol Biomarkers Prev 2007;16(3):409–15)