Meta- and Pooled Analyses of the Cytochrome P-450 1B1 Val432Leu Polymorphism and Breast Cancer: A HuGE-GSEC Review

Abstract

The association between the cytochrome P-450 1B1 (CYP1B1) Val432Leu polymorphism and breast cancer was assessed through a meta-analysis of all published case-control studies and a pooled analysis of both published and unpublished case-control studies from the Genetic Susceptibility to Environmental Carcinogens (GSEC) database ( www.upci.upmc.edu/research/ccps/ccontrol/g_intro.html ). GSEC is a collaborative project that gathers information on studies of metabolic gene polymorphisms and cancer. Thirteen articles were included in the meta-analysis (14,331 subjects; 7,514 cases, 6,817 controls); nine data sets were included in the pooled analysis (6,842 subjects; 3,391 cases, 3,451 controls). A summary meta- or pooled estimate of the association between the CYP1B1 Val432Leu polymorphism and breast cancer could not be calculated because of statistically significant heterogeneity in the point estimates among studies. No association between the CYP1B1 Val432Leu polymorphism and breast cancer was observed in Asians (for Val/Val and Val/Leu combined, odds ratio (OR) = 1.0, 95% confidence interval (CI): 0.8, 1.2). An inverse association was observed in populations of mixed/African origin (OR = 0.8, 95% CI: 0.7, 0.9). The pooled analysis suggested a possible association in Caucasians (for Val/Val and Val/Leu combined, OR = 1.5, 95% CI: 1.1, 2.1), with effect modification across age categories. The observed effect of age on the association in Caucasians indicates that further studies are needed on the role of CYP1B1 Val432Leu in estrogen metabolism according to age, ethnicity, and menopausal status.

Genetic polymorphisms in estrogen metabolism and breast cancer risk in case–control studies in Japanese, Japanese Brazilians and non-Japanese Brazilians

“…These results are inconsistent with those reported for Asians in the meta-analysis. 24 Previous studies have demonstrated that the Val allele contributes to an increase in 4-hydroxylation activity and a lower urinary 2-OHEs/16a-OHEs ratio (Table 1), whereas the Leu allele contributes to an increase in procarcinogen activation. 2,16,34 Our results might be explained by the latter mechanism.…”

“…2,24 A recent meta-analysis demonstrated that Val allele carriers have a lower risk of breast cancer than Leu/Leu carriers among women of mixed/African ethnicity, but that there is no difference in Asians. 24 In the present study, Val allele carriers tended to have a decreased risk in the three populations combined and a significantly decreased risk among JJ. These results are inconsistent with those reported for Asians in the meta-analysis.…”

“…Several functional SNPs in these genes have been identified, consisting of variant alleles with higher (CYP1A1*2A, CYP1A1*2C, CYP1B1 Arg 48 Gly and CYP1B1 Leu 432 Val) 2 or lower or deficient activities (CYP1A2*1F and CYP3A5*3) 11,12 (Table 1). Although a relatively large number of studies have examined associations between these SNPs and the risk of breast cancer, 2,13,15,24,25 no study has examined the association between functional SNPs in the CYP3A5 gene and the risk of breast cancer, notwithstanding that CYP3A5*3 causes a splicing defect and decrease in the expression of functional CYP3A5 protein. 12 Here, to investigate the associations between breast cancer risk and six functional SNPs (CYP1A1*2A, CYP1A1*2C, CYP1A2*1F, CYP1B1 Arg 48 Gly, CYP1B1 Leu 432 Val and CYP3A5*3) in genes related to estrogen hydroxylation, we analyzed data from three populations within hospital-based case-control studies in Nagano, Japan and São Paulo, Brazil: Japanese living in Nagano, Japan (JJ), Japanese Brazilians living in São Paulo (JB) and non-Japanese Brazilians living in São Paulo (NJB).…”

Polymorphisms of cytochrome P450 genes in three ethnic groups from Russia

“…It is known that the patterns of the CYP1B1 polymorphic marker (rs1056836, 4326C> G, L432V) genotype frequencies distribution has significant racial differences (20)(21)(22). For Asian populations (Chinese, Japanese, Mexicans) it is very typical to observe the predominance of CYP1B1*1*1 genotype, which varies from 67 to 91% (20).…”

“…For Asian populations (Chinese, Japanese, Mexicans) it is very typical to observe the predominance of CYP1B1*1*1 genotype, which varies from 67 to 91% (20). In contrast, for Africans the most frequent genotype is CYP1B1*3*3, 68% in African Americans with the level of 87% in the Yoruba in Ibadan, Nigeria, YRI (HapMap) (20,21).…”