Human Molecular Genetics Advance Access published online on February 17, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp078
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FGFR2 variants and breast cancer risk: fine-scale mapping using African American studies and analysis of chromatin conformation
1 Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK 2 Cancer Genetics Branch, NHGRI, Bethesda, MD 3 CRUK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK, CB2 0RE 4 Laboratory of Population Genetics, National Cancer Institute, Bethesda, MD (Current Affiliation: Office of Population Genomics, NHGRI) 5 Laboratory of Population Genetics, US National Cancer Institute, Bethesda, MD 6 Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 7 Department of Oncology, University of Cambridge, Cambridge, UK 8 Department of Population Sciences, City of Hope National Medical Center, Duarte, CA 9 Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii 10 Department of Preventive Medicine, Keck School of Medicine, USC, Los Angeles, CA 11 Department of Nutrition, University of Oslo, Oslo, Norway 12 Department of Pathology, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 13 International Agency for Research on Cancer, Lyon, France 14 National Cancer Institute, Bangkok, Thailand 15 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 16 Seoul National University College of Medicine, Seoul, Korea 17 National Cancer Center, Goyang, Korea
* Corresponding Author: Douglas F. Easton Email: douglas.easton{at}srl.cam.ac.uk Strangeways Research Laboratory Worts Causeway Cambridge CB1 8RN Phone: (+44) 1223 740 160 Fax: (+44) 1223 740 159
Received December 16, 2008; Revised February 9, 2009; Accepted February 13, 2009
Genome wide association studies have identified FGFR2 as a breast cancer (BC) susceptibility gene in populations of European and Asian descent, but a causative variant has not yet been conclusively identified. We hypothesized that the weaker linkage disequilibrium across this associated region in populations of African ancestry might help refine the set of candidate causal SNPs previously identified by our group. Eight candidate causal SNPs were evaluated in 1,253 African American invasive BC cases and 1,245 controls. A significant association with BC risk was found with SNP rs2981578 (unadjusted per allele odds ratio (OR)=1.20, 95% confidence interval (CI) 1.03-1.41, Ptrend=0.02), with the estimate similar to that reported in European and Asian subjects. To extend the fine-mapping, genotype data from the African American studies were analyzed jointly with data from European (n=7,196 cases, 7,275 controls) and Asian (n=3,901 cases, 3,205 controls) studies. In the combined analysis, SNP rs2981578 was the most strongly associated. Five other SNPs were too strongly correlated to be excluded at a likelihood ratio of <1/100 relative to rs2981578. Analysis of DNase I hypersensitive sites indicated that only two of these map to accessible chromatin, one of which, SNP rs2981578, has previously been implicated in up-regulating FGFR2 expression. Our results demonstrate that the association of SNPs in FGFR2 with BC risk extends to women of African American ethnicity, and illustrate the utility of combining association analysis in datasets of diverse ethnic groups with functional experiments to identify disease susceptibility variants.
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