title: A signature of balancing selection in the region upstream to the human UGT2B4 gene and implications for breast cancer risk.
abstract: 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 (4.8 kb 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.
authors.affiliation: Department of Human Genetics, University of Chicago, 920 E. 58th Street, Chicago, IL 60637, USA.
authors.forename: Chang
authors.initials: C
authors.lastname: Sun
authors.forename: Dezheng
authors.initials: D
authors.lastname: Huo
authors.forename: Catherine
authors.initials: C
authors.lastname: Southard
authors.forename: Barbara
authors.initials: B
authors.lastname: Nemesure
authors.forename: Anselm
authors.initials: A
authors.lastname: Hennis
authors.forename: M
authors.initials: M
authors.lastname: Cristina Leske
authors.forename: Suh-Yuh
authors.initials: SY
authors.lastname: Wu
authors.forename: David B
authors.initials: DB
authors.lastname: Witonsky
authors.forename: Olufunmilayo I
authors.initials: OI
authors.lastname: Olopade
authors.forename: Anna
authors.initials: A
authors.lastname: Di Rienzo
mesh_terms: D044383:Black People; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D060148:HapMap Project; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA
chemical_list: D014453:Glucuronosyltransferase; C486404:UGT2B4 protein, human