Context:
The risk of many conditions, including prostate cancer, breast cancer, and osteoporosis, is associated with serum levels of sex steroids.

Objective:
The aim of the study was to identify genetic variations in sex steroid-related genes that are associated with serum levels of estradiol (E2) and/or testosterone in men.

Design:
Genotyping of 604 single nucleotide polymorphisms in 50 sex steroid-related candidate genes was performed in the Gothenburg Osteoporosis and Obesity Determinants (GOOD) study (n=1041 men; age, 18.9±0.6yr). Replications of significant associations were performed in the Osteoporotic Fractures in Men (MrOS) Sweden study (n=2568 men; age, 75.5±3.2yr) and in the MrOS US study (n=1922 men; age, 73.5±5.8yr). Serum E2, testosterone, and estrone (E1) levels were analyzed using gas chromatography/mass spectrometry.

Results:
The screening in the GOOD cohort identified the single nucleotide polymorphism rs2470152 in intron 1 of the CYP19 gene, which codes for aromatase, responsible for the final step of the biosynthesis of E2 and E1, to be most significantly associated with serum E2 levels (P=2×10−6). This association was confirmed both in the MrOS Sweden study (P=9×10−7) and in the MrOS US study (P=1×10−4). When analyzed in all subjects (n=5531), rs2470152 was clearly associated with both E2(P=2×10−14) and E1 (P=8×10−19) levels. In addition, this polymorphism was modestly associated with lumbar spine BMD (P<0.01) and prevalent self-reported fractures (P<0.05).

Conclusions:
rs2470152 of the CYP19 gene is clearly associated with serum E2 and E1 levels in men (Table 4).