caa a22 4500 445860634 CHVBK 20180317145441.0 cr unu---uuuuu 170323e20111201xx s 000 0 eng 10.1007/s00439-011-1025-6 doi (NATIONALLICENCE)springer-10.1007/s00439-011-1025-6 A signature of balancing selection in the region upstream to the human UGT2B4 gene and implications for breast cancer risk [Elektronische Daten] [Chang Sun, Dezheng Huo, Catherine Southard, Barbara Nemesure, Anselm Hennis, M. Cristina Leske, Suh-Yuh Wu, David Witonsky, Olufunmilayo Olopade, Anna Di Rienzo] UDP-glucuronosyltransferase 2 family, polypeptide B4 (UGT2B4) is an important metabolizing enzyme involved in the clearance of many xenobiotics and endogenous substrates, especially steroid hormones and bile acids. The HapMap data show that numerous SNPs upstream of UGT2B4 are in near-perfect linkage disequilibrium with each other and occur at intermediate frequency, indicating that this region might contain a target of natural selection. To investigate this possibility, we chose three regions (4.8kb in total) for resequencing and observed a striking excess of intermediate-frequency alleles that define two major haplotypes separated by many mutation events and with little differentiation across populations, thus suggesting that the variation pattern upstream UGT2B4 is highly unusual and may be the result of balancing selection. We propose that this pattern is due to the maintenance of a regulatory polymorphism involved in the fine tuning of UGT2B4 expression so that heterozygous genotypes result in optimal enzyme levels. Considering the important role of steroid hormones in breast cancer susceptibility, we hypothesized that variation in this region could predispose to breast cancer. To test this hypothesis, we genotyped tag SNP rs13129471 in 1,261 patients and 825 normal women of African ancestry from three populations. The frequency comparison indicated that rs13129471 was significantly associated with breast cancer after adjusting for ethnicity [P=0.003; heterozygous odds ratio (OR) 1.02, 95% confidence interval (CI) 0.81-1.28; homozygous OR 1.50, 95% CI 1.15-1.95]. Our results provide new insights into UGT2B4 sequence variation and indicate that a signal of natural selection may lead to the identification of disease susceptibility variants. Springer-Verlag, 2011 Sun Chang Department of Human Genetics, University of Chicago, 920 E. 58th Street, 60637, Chicago, IL, USA aut Huo Dezheng Department of Health Studies, University of Chicago, 60637, Chicago, IL, USA aut Southard Catherine Department of Human Genetics, University of Chicago, 920 E. 58th Street, 60637, Chicago, IL, USA aut Nemesure Barbara Department of Preventive Medicine, State University of New York at Stony Brook, 11794, Stony Brook, NY, USA aut Hennis Anselm Faculty of Medical Sciences, University of the West Indies, Bridgetown, Barbados aut Cristina Leske M. Department of Preventive Medicine, State University of New York at Stony Brook, 11794, Stony Brook, NY, USA aut Wu Suh-Yuh Department of Preventive Medicine, State University of New York at Stony Brook, 11794, Stony Brook, NY, USA aut Witonsky David Department of Human Genetics, University of Chicago, 920 E. 58th Street, 60637, Chicago, IL, USA aut Olopade Olufunmilayo Department of Medicine, University of Chicago, 60637, Chicago, IL, USA aut Di Rienzo Anna Department of Human Genetics, University of Chicago, 920 E. 58th Street, 60637, Chicago, IL, USA aut Human Genetics Springer-Verlag 130/6(2011-12-01), 767-775 0340-6717 130:6<767 2011 130 439 https://doi.org/10.1007/s00439-011-1025-6 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00439-011-1025-6 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Sun Chang Department of Human Genetics, University of Chicago, 920 E. 58th Street, 60637, Chicago, IL, USA aut NATIONALLICENCE 700 1- Huo Dezheng Department of Health Studies, University of Chicago, 60637, Chicago, IL, USA aut NATIONALLICENCE 700 1- Southard Catherine Department of Human Genetics, University of Chicago, 920 E. 58th Street, 60637, Chicago, IL, USA aut NATIONALLICENCE 700 1- Nemesure Barbara Department of Preventive Medicine, State University of New York at Stony Brook, 11794, Stony Brook, NY, USA aut NATIONALLICENCE 700 1- Hennis Anselm Faculty of Medical Sciences, University of the West Indies, Bridgetown, Barbados aut NATIONALLICENCE 700 1- Cristina Leske M. Department of Preventive Medicine, State University of New York at Stony Brook, 11794, Stony Brook, NY, USA aut NATIONALLICENCE 700 1- Wu Suh-Yuh Department of Preventive Medicine, State University of New York at Stony Brook, 11794, Stony Brook, NY, USA aut NATIONALLICENCE 700 1- Witonsky David Department of Human Genetics, University of Chicago, 920 E. 58th Street, 60637, Chicago, IL, USA aut NATIONALLICENCE 700 1- Olopade Olufunmilayo Department of Medicine, University of Chicago, 60637, Chicago, IL, USA aut NATIONALLICENCE 700 1- Di Rienzo Anna Department of Human Genetics, University of Chicago, 920 E. 58th Street, 60637, Chicago, IL, USA aut NATIONALLICENCE 773 0- Human Genetics Springer-Verlag 130/6(2011-12-01), 767-775 0340-6717 130:6<767 2011 130 439 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer