A novel polymorphism in the 17β-hydroxysteroid dehydrogenase type 5 (aldo-keto reductase 1C3) gene is associated with lower serum testosterone levels in caucasian men

Abstract

Genetic variation in the androgen metabolizing enzymes is important to identify and feature as they may influence the risk of prostate cancer and help clarify the etiology of the disease. Human 17b-hydroxysteroid dehydrogenase type 5 (AKR1C3) is highly expressed in the prostate gland and plays a major role in the formation and metabolism of androgens. We identified five novel polymorphisms in the AKR1C3 gene. One of those an A4G substitution in exon 2 that confers a Glu77Gly change occurred in 4.8% in Caucasians but was completely absent in Orientals. Interestingly, the testosterone level in serum was significantly lower in subjects with the Gly77 allele. A promoter A4G polymorphism was associated with significantly altered promoter activity in reporter constructs, but was not associated with any change in testosterone levels. In conclusion, the Glu77Gly polymorphism is associated with lower testosterone levels in serum.

Analysis of 17β-hydroxysteroid dehydrogenase types 5, 7, and 12 genetic sequence variants in breast cancer cases from French Canadian Families with high risk of breast and ovarian cancer

“…1, Panel D). Jakobsson et al reported an association between the p.Glu77Gly polymorphism and lowered serum testosterone levels in men [67]. Functional analysis performed in the study also revealed a tendency for decreased activity of the polymorphic Gly77 enzyme, although this difference was not significant.…”

“…1(Panels C and D), the current study shows a lack of effect of the p.His5Gln variation on enzymatic activity. Another non-synonymous variant, p.Glu77Gly, was previously reported to be associated with circulating testosterone levels [67]. As discussed previously, the assessment of the effect of this variant on the enzymatic activity of the 17␤-HSD type 5 enzyme revealed a slightly significant difference in the conversion levels of androstenedione as compared to the wild-type enzyme (Fig.…”

Effect of Polymorphisms in Selected Genes Involved in Pituitary-Testicular Function on Reproductive Hormones and Phenotype in Aging Men

“…We have reported previously from the EMAS cohort associations of the AR exon 1 CAG repeat polymorphism with endocrine and metabolic parameters (23), and of AR exon 1 CAG repeat and other polymorphisms with heel ultrasound parameters (8). Other genes with polymorphisms associated with androgen and/or estrogen levels in men include SHBG (28), CYP17 (29), CYP19A1 (30), 17␤HSD5 (31), and uridine diphosphate glucuronyltransferase 2B7 (UGT2B7) (32), but many potentially important polymorphic influences have apparently not yet been identified.…”

Polymorphism Thr160Thr in SRD5A1, involved in the progesterone metabolism, modifies postmenopausal breast cancer risk associated with menopausal hormone therapy

“…AKR1C3 expression was observed to be most prominent in the prostate and mammary gland and is in the position to control estrogen action at the receptor level [39][40][41]. AKR1C3_rs7741 is in perfect LD with AKR1C3_rs3763676 (r 2 = 1.00), for which a lower transcriptional enzyme activity for minor allele carriers was observed [42]. Decreased activity of the enzyme leading to less reduction of estrone to 17b-estradiol appears compatible with our observation of a more pronounced risk increase associated with duration of monotherapy use in homozygous carriers of the minor A allele of AKR1C3_rs7741 (Table 3; Online Resources 3 and 5).…”