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Twin studies suggest a heritable component to circulating sex steroid hormones and sex hormone-binding globulin (SHBG). In the NCI-Breast and Prostate Cancer Cohort Consortium, 874 SNPs in 37 candidate genes in the sex steroid hormone pathway were examined in relation to circulating levels of SHBG (N= 4720), testosterone (N= 4678), 3α-androstanediol-glucuronide (N= 4767) and 17β-estradiol (N= 2014) in Caucasian men. rs1799941 inSHBGis highly significantly associated with circulating levels of SHBG (P= 4.52 × 10−21), consistent with previous studies, and testosterone (P= 7.54 × 10−15), with mean difference of 26.9 and 14.3%, respectively, comparing wild-type to homozygous variant carriers. Further noteworthy novel findings were observed between SNPs inESR1with testosterone levels (rs722208, mean difference = 8.8%,P= 7.37 × 10−6) andSRD5A2with 3α-androstanediol-glucuronide (rs2208532, mean difference = 11.8%,P= 1.82 × 10−6). Genetic variation in genes in the sex steroid hormone pathway is associated with differences in circulating SHBG and sex steroid hormones.

Quantitative trait loci predicting circulating sex steroid hormones in men from the NCI-Breast and Prostate Cancer Cohort Consortium (BPC3)