Genes regulating estradiol and estrone-conjugate levels in postmenopausal women with resected early-stage breast cancer detected by a genome-wide association study (GWAS).

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1001 Background: There is large inter-individual variation in baseline estrone (E1), estradiol (E2), E1-conjugate (E1-C), androstenedione (A), and testosterone (T) levels in postmenopausal women with resected early stage breast cancer (Ingle et al., Ca Res 70:3278−86, 2010). We hypothesized that genetic variation can explain some of this variation in baseline (before anastrozole) hormone levels and performed a GWAS. Methods: Baseline plasma was obtained for E1, E2, E1-C, A, and T assays by GC-MS-MS. Genotypes were determined with the Illumina Human610-Quad BeadChip. Eigenstrat analyses were performed to control for population stratification (PS). Analysis of each baseline hormone level was assessed with each genotype using a quasi-likelihood model because of the skewness in baseline hormone levels, with adjustment for PS as well as body mass index, age and any additional clinical variables associated with baseline hormone levels (p<0.01). SNPs were imputed within 200 Kb on either side of regions containing SNPs with p < 3E-05 using HapMap. Results: 563,945 SNPs were used in the analyses. SNP genotypes were modeled in terms of the number of minor alleles (0, 1 or 2), with SNPs achieving genome-wide significance after Bonferroni correction (p<5E-08) identified for both E2 and E1-C. For E2 (n=757 patients), the genotyped SNP (rs1864729) with the lowest p-value (p=1.13E-08) was on chromosome (chr) 8 and had a multiplicative effect (ME: estimated fold change per minor allele) of 1.62 (95% CI: 1.38, 1.91), with the closest gene being TSPYL5 (Testis-specific Y-encoded-like protein 5), which we showed to be regulated by E2. There were 8 imputed SNPs near rs1864729 with lower p-values (1.03E-08-3.85E-09). For E1-C (n=752 patients), one nonsynonymous SNP (rs4149056) on chr 12 in the SLCO1B1 gene (which encodes an E1-C transporter) was significant (p=5E-08) with ME 1.41 (95% CI: 1.25, 1.60). Conclusions: This GWAS revealed novel loci associated with the baseline levels of E2 and E1-C in postmenopausal women that may be of importance for understanding the estrogen physiology of postmenopausal women and their response to aromatase inhibitor therapy.