Abstract LB-404: Genome-wide association study of circulating estradiol, testosterone, and sex hormone-binding globulin levels in postmenopausal women

Abstract

Abstract Factors that influence endogenous and exogenous exposure to steroid hormones are associated with increased cancer risk of hormonally regulated tissues. Epidemiologic studies indicate that high circulating estrogens and androgens are strongly associated with increased postmenopausal breast cancer risk. Conversely, higher levels of sex hormone-binding globulin (SHBG), which binds to estrogens and androgens with high affinity, may be associated with reduced breast cancer risk. The regulation of plasma levels of sex steroid hormones is complex and not fully understood. Therefore, genetic variants not within candidate gene regions may be associated with sex hormone levels. To identify such variants, we used existing data on 528,173 SNPs genotyped on the Illumina HumanHap500 array as part of the NCI Cancer Genetic Markers of Susceptibility Project to conduct genome-wide association analyses among the subset of Nurses’ Health Study (NHS) postmenopausal women (N=1377) with measured levels of estradiol (E2), testosterone (T), and SHBG. Analyses were stratified by postmenopausal hormone use at blood draw. Generalized linear models of the log transformed hormone levels were adjusted for age at blood draw and laboratory batch. We used weighted Z scores to generate p-values for the combined effect of the two groups. Independent single nucleotide polymorphisms (SNPs) with the smallest p-values for E2 (N=48), T (N=35), and SHBG (N=45) were genotyped in a different set of women with measured hormone levels from the NHS (N=619). An additional 359 women from CGEMS who only had SHBG data available were added to the replication set. No SNP association reached the GWAS significance threshold of 5 × 10-08. The SNP most strongly associated with SHBG levels was rs2955617 (joint Ptrend = 2.3 × 10-07), which is located on chromosome 17, ∼2 kb downstream of the SHBG gene. The subsequent 4 SNPs with the smallest joint Ptrend values (rs1010889 = 1.3 × 10-06, rs10822129 = 3.6 × 10-06, rs10509186 = 9.2 × 10-06, rs7923609 = 1.6 × 10-05) identify a locus on chromosome 10 containing the NRBF2 and JMJD1C genes, both of which have some evidence of modulating nuclear receptor activity. SNPs most strongly associated with E2 levels were located within potassium channel genes: KCNMA1 on chromosome 10 (joint Ptrend for rs10509385 = 2.4 × 10-06) and KCTD1 on chromosome 18 (joint Ptrend for rs4480883 = 9.9 × 10-06). For T levels, the most strongly associated SNPs were located on chromosome 7 within the MAGI2 gene (joint Ptrend for rs7787781 = 6.0 × 10-06) and chromosome 1 near the WNT2B/ST7L locus (joint Ptrend for rs11102457 = 9.6 × 10-06). These results provide some evidence for the association of genetic variation in the vicinity of a candidate gene as well as novel loci with steroid hormone levels. Additional replication and meta-analysis with other genome-wide association studies are needed to verify these findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-404.