Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 (UGT1A1) and risk of breast cancer

Abstract

Uridine diphospho-glucuronosyltransferase 1A1 (UGT1A1) is involved in catalyzing estrogen, the hormone that plays a central role in the etiology of breast cancer. A common polymorphism [A(TA)6TAA (allele *1) to A(TA)7TAA change (allele *28)] in the TATA-box of the promoter region of the UGT1A1 gene has been reported to be associated with a reduced transcription of this gene. We investigated the association of this polymorphism with the risk of breast cancer among 1047 breast cancer cases and 1083 community controls in the Shanghai Breast Cancer Study, a population-based case-control study. Approximately same proportion of cases (12.5%) and controls (13.0%) carried the variant allele *28 in the Chinese population (p = 0.32). When stratified by age, carrying the *28 allele was associated with an increased risk of breast cancer among women aged less than 40 years (odds ratio [OR] = 1.7; 95% CI = 1.0-2.7) but not among women 40 years old and over (OR = 0.8; 0.7-1.1). Only a few women were homozygous for the *28 allele, precluding a detailed gene-dose association analysis. Additional analyses showed that, the elevated risk associated with the UGT1A1 *28 allele among young women was primarily seen in women who had a later menarche, short menstrual years, absence of family history of breast cancer, low waist-to-hip ratio, or low body-mass index. These results suggested that the *28 allele in the UGT1A1 gene may be associated with an increased risk for breast cancer among Chinese women under age 40. No significant associations were observed with *28 allele and breast cancer risk by estrogen receptor/progesterone receptor status.

Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 and breast cancer risk in Africans

“…We found the distribution of TA repeat genotypes was significantly different between cases and controls, but the patterns were not systematic in the overall analysis. In contrast to the two previous studies conducted in African Americans [4] and in Chinese [8], which found that 7 or 8 allele-containing genotypes were associated with elevated risk of breast cancer in premenopausal women [4] or women younger than 40 years [8], we found that these low activity 7 or 8 allele-containing genotypes were associated with decreased risk of breast cancer among premenopausal women or those younger than 45 years old.…”

“…Previous studies have observed that the wild-type allele (UGT1A1*1) was the most common allele among Caucasian, African American and Asian populations [4,6,8,[10][11][12]. We found that the variant allele UGT1A1*28 was as common as UGT1A1*1 allele, with about 40% frequency for each allele among indigenous Africans.…”

“…All previous studies [4,6,8,9] except one [7] showed that there was no overall difference between breast cancer cases and controls in the distribution of TA repeat genotypes. We found the distribution of TA repeat genotypes was significantly different between cases and controls, but the patterns were not systematic in the overall analysis.…”

“…A study conducted in Russia showed that UGT1A1*28 allele-containing genotypes were associated with breast cancer risk [7]. Adegoke et al observed that the UGT1A1*28 allele was associated with an increased risk of breast cancer among Chinese women younger than 40 years old, but not among women 40 years old or over [8]. Another study conducted in a Chinese population showed that the proportion having the UGT1A1*28 allele was similar between cases and controls [9].…”

“…The frequency of TA repeat polymorphisms varies among ethnic groups [4,6,8,[10][11][12], in particular between African and non-African populations [12,13] and this variability is suggested to be maintained by natural selection [13]. Furthermore, breast cancer is a heterogeneous disease; for example, we found hormone receptor negative breast cancer was much more common in West Africans (Olopade et al submitted) than in US populations of African Americans and non-African Americans [14].…”