CYP2B6 metabolizes many drugs, and its expression varies greatly. CYP2B6 genotype-phenotype associations were determined using human livers that were biochemically phenotyped for CYP2B6 (mRNA, protein, and CYP2B6 activity), and genotyped for CYP2B6 coding and 5Ј-flanking regions. CYP2B6 expression differed significantly between sexes. Females had higher amounts of CYP2B6 mRNA (3.9-fold, P Ͻ 0.001), protein (1.7-fold, P Ͻ 0.009), and activity (1.6-fold, P Ͻ 0.05) than did male subjects. Furthermore, 7.1% of females and 20% of males were poor CYP2B6 metabolizers. Striking differences among different ethnic groups were observed: CYP2B6 activity was 3.6-and 5.0-fold higher in Hispanic females than in Caucasian (P Ͻ 0.022) or African-American females (P Ͻ 0.038). Ten single nucleotide polymorphisms (SNPs) in the CYP2B6 promoter and seven in the coding region were found, including a newly identified 13072AϾG substitution that resulted in an Lys139Glu change. Many CYP2B6 splice variants (SV) were observed, and the most common variant lacked exons 4 to 6. A nonsynonymous SNP in exon 4 (15631GϾT), which disrupted an exonic splicing enhancer, and a SNP 15582CϾT in an intron-3 branch site were correlated with this SV. The extent to which CYP2B6 variation was a predictor of CYP2B6 activity varied according to sex and ethnicity. The 1459CϾT SNP, which resulted in the Arg487Cys substitution, was associated with the lowest level of CYP2B6 activity in livers of females. The intron-3 15582CϾT SNP (in significant linkage disequilibrium with a SNP in a putative hepatic nuclear factor 4 (HNF4) binding site) was correlated with lower CYP2B6 expression in females. In conclusion, we found several common SNPs that are associated with polymorphic CYP2B6 expression.

We carried out a genome-wide association study of breast cancer predisposition with replication and refinement studies involving 6,145 cases and 33,016 controls and identified two SNPs (rs4415084 and rs10941679) on 5p12 that confer risk, preferentially for estrogen receptor (ER)-positive tumors (OR = 1.27, P = 2.5 x 10(-12) for rs10941679). The nearest gene, MRPS30, was previously implicated in apoptosis, ER-positive tumors and favorable prognosis. A recently reported signal in FGFR2 was also found to associate specifically with ER-positive breast cancer.

Germline mutations in the BRCA1 or BRCA2 tumour-suppressor genes are strong predictors of breast and/or ovarian cancer development. The contribution of these mutations to breast cancer risk within any specific population is a function of both their prevalence and their penetrance. Mutation prevalence varies among ethnic groups and may be influenced by founder mutations. Penetrance can be influenced by mutation-specific phenotypes and the potential modifying effects of the patient's own genetic and environmental background. Although estimates of both mutation prevalence and mutation penetrance rates are inconsistent and occasionally controversial, understanding them is crucial for providing accurate risk information to each patient.