Human Molecular Genetics Advance Access published online on August 27, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn267
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Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer
1 Section of Cancer Genetics, Institute of Cancer Research, Sutton, SM2 5NG, UK 2 Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London WC2A 3PX UK 3 Family Cancer Clinic, St Mark's Hospital, Watford Road, Harrow HA1 3UJ, UK 4 Non-Communicable Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, London, UK; and Institute of Cancer Research, Surrey, UK 5 Cancer Research UK Epidemiology and Genetics Unit, Institute of Cancer Research, London, UK 6 Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK 7 Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK 8 Department of Medical and Molecular Genetics, University of Birmingham School of Medicine and West Midlands Regional Genetics Service, Birmingham Women's Hospital, Edgbaston, Birmingham, UK 9 University of Southampton and Wessex Clinical Genetics Service, Mailpoint 105, Princess Anne Hospital, Coxford Road, Southampton SO16 5YA, UK 10 Department of Clinical Pharmacology, Oxford University, Radcliffe Infirmary, Oxford, OX2 6HA, UK 11 Department of Medical Genetics, St Mary's Hospital, Manchester, M13 0JH, UK 12 Department of Pathology (TVW, HM) and Center for Human and Clinical Genetics (JTW), Leiden University Medical Center, Albinusdreef 2, 2333ZA, Leiden, The Netherlands 13 Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, 723 Swanston street, Carlton VIC 3053, Australia 14 Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Grattan street, Parkville VIC 3052, Australia 15 Cancer Epidemiology Centre, The Cancer Council Victoria, 1 Rathdowne street, Carlton VIC 3053, Australia 16 Department of Gastroenterology, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedes Hepáticas y Digestivas (CIBER-EHD), IDIBAPS, Barcelona, Catalonia, Spain 17 Genomic Medicine Group, Fundacion Publica Galega de Medicina Xenomica (FPGMX), Spanish National Genotyping Center (CeGen)-University of Santiago Compostela, CIBERER, Hospital Clínico, Santiago de Compostela, Galicia, Spain 18 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany 19 Center for Family and Community Medicine, Karolinska Institute, 141 83 Huddinge, Sweden 20 Institute of Experimental Medicine at the Academy of Sciences, Czech Rep., Videnska 1083, 14200 Prague, Czech Republic 21 Department of Medical Oncology and Clinical Haematology, Western Hospital, Footscray 3011, Victoria, Australia 22 The University of Hong Kong, Hong Kong 23 Department of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain 24 Service of Gastroenterology. San Carlos University Hospital, Madrid, Spain 25 Molecular Oncology Laboratory, Hospital San Carlos, 28040 Madrid, Spain 26 Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland 27 Bioinformatics and Biostatistics, London Research Institute, Cancer Research UK, London WC2A 3PX, UK
Correspondence should be addressed to: Richard S Houlston, Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey. SM2 5NG. Tel: +44 (0) 208 722 4175 Fax: +44 (0) 208 722 4365 e-mail: Richard.houlston{at}icr.ac.uk
Received June 6, 2008; Revised July 24, 2008; Accepted August 24, 2008
The common single nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10,638 cases and 10,457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR =1.17; 95% confidence interval [CI]: 1.12–1.22; P=1.08 x 10–12) with the risk allele more frequent in rectal than colonic disease (P=0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants the risk of CRC increases with an increasing numbers of variant alleles for the six loci (ORper allele=1.19; 95% CI: 1.15-1.23; Ptrend =7.4 x 10–24). Using data from our genome-wide association study of CRC, LD mapping and imputation we were able to refine the location of the causal locus to a 60Kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression
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