A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation

Coviello, Andrea D. and Haring, Robin and Wellons, Melissa and Vaidya, Dhananjay and Lehtimäki, Terho and Zhai, Guangju (2012) A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation. PLoS ONE, 7 (6). pp. 1-12. ISSN 1932-6203

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Abstract

Genome-wide association studies (GWAS) have successfully identified common genetic variants that contribute to breast cancer risk. Discovering additional variants has become difficult, as power to detect variants of weaker effect with present sample sizes is limited. An alternative approach is to look for variants associated with quantitative traits that in turn affect disease risk. As exposure to high circulating estradiol and testosterone, and low sex hormone-binding globulin (SHBG) levels is implicated in breast cancer etiology, we conducted GWAS analyses of plasma estradiol, testosterone, and SHBG to identify new susceptibility alleles. Cancer Genetic Markers of Susceptibility (CGEMS) data from the Nurses' Health Study (NHS), and Sisters in Breast Cancer Screening data were used to carry out primary meta-analyses among ~1600 postmenopausal women who were not taking postmenopausal hormones at blood draw. We observed a genome-wide significant association between SHBG levels and rs727428 (joint β = -0.126; joint P = 2.09×10 -16), downstream of the SHBG gene. No genome-wide significant associations were observed with estradiol or testosterone levels. Among variants that were suggestively associated with estradiol (P<10 -5), several were located at the CYP19A1 gene locus. Overall results were similar in secondary meta-analyses that included ~900 NHS current postmenopausal hormone users. No variant associated with estradiol, testosterone, or SHBG at P<10 -5 was associated with postmenopausal breast cancer risk among CGEMS participants. Our results suggest that the small magnitude of difference in hormone levels associated with common genetic variants is likely insufficient to detectably contribute to breast cancer risk.

Item Type: Article
URI: http://research.library.mun.ca/id/eprint/514
Item ID: 514
Additional Information: * et al.: Sarah Keildson, Kathryn L. Lunetta, Chunyan He, Myriam Fornage, Vasiliki Lagou, Massimo Mangino, N. Charlotte Onland-Moret, Brian Chen, Joel Eriksson, Melissa Garcia, Yong Mei Liu, Annemarie Koster, Kurt Lohman, Leo-Pekka Lyytikäinen, Ann-Kristin Petersen, Jennifer Prescott, Lisette Stolk, Liesbeth Vandenput, Andrew R. Wood, Wei Vivian Zhuang, Aimo Ruokonen, Anna-Liisa Hartikainen, Anneli Pouta, Stefania Bandinelli, Reiner Biffar, Georg Brabant, David G. Cox, Yuhui Chen, Steven Cummings, Luigi Ferrucci, Marc J. Gunter, Susan E. Hankinson, Hannu Martikainen, Albert Hofman, Georg Homuth, Thomas Illig, John-Olov Jansson, Andrew D. Johnson, David Karasik, Magnus Karlsson, Johannes Kettunen, Douglas P. Kiel, Peter Kraft, Jingmin Liu, Östen Ljunggren, Mattias Lorentzon, Marcello Maggio, Marcello R. P. Markus, Dan Mellström, Iva Miljkovic, Daniel Mirel, Sarah Nelson, Laure Morin Papunen, Petra H. M. Peeters, Inga Prokopenko, Leslie Raffel, Martin Reincke, Alex P. Reiner, Kathryn Rexrode, Fernando Rivadeneira, Stephen M. Schwartz, David Siscovick, Nicole Soranzo, Doris Stöckl, Shelley Tworoger, André G. Uitterlinden, Carla H. van Gils, Ramachandran S. Vasan, H.-Erich Wichmann, Shalender Bhasin, Martin Bidlingmaier, Stephen J. Chanock, Immaculata De Vivo, Tamara B. Harris, David J. Hunter, Mika Kähönen, Simin Liu, Pamela Ouyang, Tim D. Spector, Yvonne T. van der Schouw, Jorma Viikari, Henri Wallaschofski, Mark I. McCarthy, Timothy M. Frayling, Anna Murray, Steve Franks, Marjo-Riitta Järvelin, Frank H. de Jong, Olli Raitakari, Alexander Teumer, Claes Ohlsson, Joanne M. Murabito, John R. B. Perry
Keywords: adult; allele; article; breast cancer; cancer risk; clinical study; cohort analysis; estradiol blood level; female; gene locus; genetic association; genetic susceptibility; genetic variability; hormone substitution; human; meta analysis (topic); postmenopause; prospective study; protein blood level; quantitative trait; testosterone blood level
Department(s): Medicine, Faculty of
Date: 4 June 2012
Date Type: Publication

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