Human Molecular Genetics Advance Access originally published online on February 17, 2009
Human Molecular Genetics 2009 18(9):1692-1703; 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 and 2 Department of Oncology, University of Cambridge, Cambridge, UK 3 Cancer Genetics Branch, NHGRI, Bethesda, MD, USA 4 CRUK Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK 5 Laboratory of Population Genetics, US National Cancer Institute, Bethesda, MD, USA 6 Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA 7 Department of Population Sciences, City of Hope National Medical Center, Duarte, CA, USA 8 Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii 9 Department of Preventive Medicine, Keck School of Medicine, USC, Los Angeles, CA, USA 10 Department of Pathology, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA 11 Department of Nutrition, University of Oslo, Oslo, Norway 12 International Agency for Research on Cancer, Lyon, France 13 National Cancer Institute, Bangkok, UK 14 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC 15 Seoul National University College of Medicine, Seoul, Korea and 16 National Cancer Center, Goyang, Korea
* To whom correspondence should be addressed at: Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK. Tel: +44 1223 740 160; Fax: +44 1223 740 159; Email: douglas.easton{at}srl.cam.ac.uk
Received December 16, 2008; 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 single nucleotide polymorphisms (SNPs) previously identified by our group. Eight candidate-causal SNPs were evaluated in 1253 African American invasive BC cases and 1245 controls. A significant association with BC risk was found with SNP rs2981578 (unadjusted per-allele odds ratio = 1.20, 95% confidence interval 1.03–1.41, Ptrend = 0.02), with the odds ratio 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 = 7196 cases, 7275 controls) and Asian (n = 3901 cases, 3205 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 highly 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.
Current address: Office of Population Genomics, NHGRI.
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