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

Abstract

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), 3 alpha-androstanediol-glucuronide (N = 4767) and 17beta-estradiol (N = 2014) in Caucasian men. rs1799941 in SHBG is highly significantly associated with circulating levels of SHBG (P = 4.52 x 10(-21)), consistent with previous studies, and testosterone (P = 7.54 x 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 in ESR1 with testosterone levels (rs722208, mean difference = 8.8%, P = 7.37 x 10(-6)) and SRD5A2 with 3 alpha-androstanediol-glucuronide (rs2208532, mean difference = 11.8%, P = 1.82 x 10(-6)). Genetic variation in genes in the sex steroid hormone pathway is associated with differences in circulating SHBG and sex steroid hormones.

Figure 1.

Sex steroid metabolism. In males, testosterone (T), carried by SHBG, is ultimately converted to the active metabolite dihydrotestosterone (DHT) by SRD5A (steroid-5-alpha-reductase), which binds to the androgen receptor (AR) with greater affinity than testosterone, leading to the activation of the transcription factor function of the androgen receptor. DHT is inactivated in the prostate by HSD3B (hydroxy-delta-5-steroid dehydrogenase) to 3α-androstanediol-glucuronide (3α-diol-G). In the prostate, testosterone is converted by aromatase (CYP19A) to estradiol (E), which further interacts with estrogen receptors (ESR).

Figure 2.

Median (inter-quartile range) levels of SHBG and sex steroids according to age, BMI, cohort and prostate cancer case–control status in the NCI-BPC3.

Figure 3.

Associations of SNPs in sex hormone metabolizing genes with blood sex hormone concentrations in the NCI-BPC3. P-values (1 df test) for association of SNPs with circulating sex steroid levels SHBG (A), testosterone (B), 3α-androstanediol-glucuronide (C) and 17β-estradiol (D). The closed circles represent genotyped SNPs and the empty circles represent imputed SNPs.

Figure 3.

Associations of SNPs in sex hormone metabolizing genes with blood sex hormone concentrations in the NCI-BPC3. P-values (1 df test) for association of SNPs with circulating sex steroid levels SHBG (A), testosterone (B), 3α-androstanediol-glucuronide (C) and 17β-estradiol (D). The closed circles represent genotyped SNPs and the empty circles represent imputed SNPs.

Figure 4.

Associations of SNPs in the SHBG region with circulating SHBG and testosterone concentrations in the NCI-BPC3. P-values (1 df test) for association of SHBG SNPs with circulating SHBG (blue circles) and testosterone (red diamonds) levels. The closed circles or diamonds represent genotyped SNPs and the empty circles or diamonds represent imputed SNPs. LD plot at the bottom is based on the measure D′ and LOD (bright red, D′ = 1 and LOD score ≥2; shades of pink/red, D′< 1 and LOD score ≥2; white, D′ < 1 and LOD score<2; blue, D′ = 1 and LOD < 2).

Figure 5.

Associations of tagSNPs in the ESR1 region with circulating testosterone concentrations in the NCI-BPC3. The closed circles represent genotyped SNPs and the empty circles represent imputed SNPs. LD plot at the bottom is based on the measure D′ and LOD (bright red, D′ = 1 and LOD score ≥2; shades of pink/red, D′< 1 and LOD score ≥2; white, D′< 1 and LOD score<2; blue, D′ = 1 and LOD<2). *Four strongest genotyped SNPs, by P-value, were rs722208, rs3020411, rs926778 and rs2348078 (in order from left to right).