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.

Association between UDP‐glucuronosyltransferase 2B7 tagSNPs and breast cancer risk in Chinese females

“…Moreover, the rs13129471 A>G polymorphism of UGT2B4 was significantly associated with breast cancer after adjusting for ethnicity. 22 This study indicates that UGT2B7 tagSNPs may influence individual susceptibility to breast cancer in the Chinese Han population.…”

“…Lin et al showed that the UGT2B7 C802T polymorphism was associated with bladder cancer in benzidine‐exposed workers in China. Moreover, the rs13129471 A>G polymorphism of UGT2B4 was significantly associated with breast cancer after adjusting for ethnicity . Scherer et al observed an association between a UGT2B15 polymorphism and increased risk of colorectal cancer.…”

Prediction of heterogeneous differential genes by detecting outliers to a Gaussian tight cluster

“…Figure 5 shows the top 25 predictions of hDEGs using DOG for this data set. Existing literature have established these genes to be of biological relevance to the progression and treatment of breast cancer ( [14-23]).…”

UGT2B4 previously implicated in the risk of breast cancer is associated with menarche timing in Ukrainian females

“…Haplotype H8 (Table S5), which was detected in 70% of the Ukrainian sample, was strongly associated with earlier AAM. Interestingly, rs13111134 is located closely to rs13129471 whose allele G was significantly associated with predisposition to breast cancer in the African population (Sun et al, 2011). Sun et al (2011) suggested the G allele of rs13129471 was associated with lower UGT2B4 expression and, respectively, higher steroid hormone concentration that promotes breast tumour development.…”

“…Interestingly, rs13111134 is located closely to rs13129471 whose allele G was significantly associated with predisposition to breast cancer in the African population (Sun et al, 2011). Sun et al (2011) suggested the G allele of rs13129471 was associated with lower UGT2B4 expression and, respectively, higher steroid hormone concentration that promotes breast tumour development. Early AAM is a known risk factor for breast cancer (McPherson et al, 2000).…”