5α‐Reductase type 2 gene variant associations with prostate cancer risk, circulating hormone levels and androgenetic alopecia

Abstract

Controversy exists over the significance of associations between the SRD5A2 (5a-reductase type 2) polymorphisms, A49T and V89L, and risk of prostate cancer. These potentially functional polymorphisms may alter life-long exposure to androgens with subsequent effects on male health and aging. The aim of this study was to examine the association of these variants with prostate cancer risk, plasma hormone levels and androgenetic alopecia. Subjects include 827 cases and 736 controls from an Australian population-based case-control study of prostate cancer. Information on prostate cancer risk factors and patterns of balding were collected. Plasma levels of testosterone, 3a-diol glucuronide (3a-diolG), dehydroepiandrosterone sulfate, androstenedione, sex hormone-binding globulin and estradiol were measured for controls. No associations with the V89L polymorphism were found. Carriers of the rarer A49T A allele were at a 60% higher risk of prostate cancer (OR 5 1.60; 95% CI 1.09-2.36; p 5 0.02) and 50% lower risk of vertex and frontal balding (p 5 0.03) compared with men homozygous for the more common G allele. Although we found little evidence of association between this variant and plasma levels of 5 measured androgens, circulating 3a-diolG levels were 34% lower in A49T A allele carriers (p < 0.0001). Our study provides evidence that the SRD5A2 A49T A variant is associated with an increased risk of prostate cancer, lower levels of circulating 3a-diolG and decreased risk of baldness. These findings raise important questions with respect to previous assumptions concerning hormonal influences on prostate cancer risk in ageing males. ' 2006 Wiley-Liss, Inc.Key words: SRD5A2; polymorphisms; prostate cancer risk; population-based case-control study; plasma androgens; androgenetic alopecia Membrane-bound 5a-reductase type 2 (SRD5A2) is responsible for the irreversible conversion of testosterone into its more active metabolite, dihydrotestosterone (DHT) and is essential for the normal growth and development of the prostate gland.1 This hormone-regulator has been implicated in male pathophysiology, including prostate cancer and balding (androgenetic alopecia). The ratio of DHT to testosterone has been reported to be highest for African-Americans, intermediate for Europeans and lowest for Asian-Americans, which corresponds to reported ethnic-based risk of prostate cancer for these groups, suggesting an association with prostate cancer risk.2 Prostate cancer risk has been associated with vertex pattern balding.3 Increased levels of DHT have been demonstrated in the male balding scalp, 4 while lack of balding is seen in pseudohermaphrodites (men with congenital 5a reductase deficiency) with a concomitant reduced ability to convert testosterone to DHT.5 DHT in turn is metabolized to 5a-androstane-3a-17b-diol glucuronide (3a-diolG), a predictor of both cutaneous and intraprostatic serum 5a-reductase levels. 6 These observations support the ''androgen hypothesis'' that increases in active androgens (and their metabolites) are associ...

Age-Dependent Associations between Androgenetic Alopecia and Prostate Cancer Risk

“…Another recent case-control study reported similar results, with combined frontal and vertex androgenetic alopecia at age 40 years associated with a reduction in odds of prostate cancer of 39% (16). It has been observed that carriers of a rare allele in the A49T polymorphism of the 5a-reductase type II gene are at greater risk of prostate cancer and a reduced risk of androgenetic alopecia (25). While this is consistent with an inverse association between androgenetic alopecia and prostate cancer risk, the evidence linking the polymorphism to prostate cancer risk is very weak.…”

Polymorphism of the SRD5A2 gene and the risk of prostate cancer

“…It has been reported that males with the VL and LL genotypes in comparison with those with the VV genotype exhibited a lower serum level of 3a-diolG (22). Conversely, Hayes et al (40) found no evidence of association between the SRD5A2 V89L polymorphism and testosterone, androstenedione, sex hormone-binding globulin or circulating levels of 3a-diolG and the risk of prostate cancer. The results of the study by Hayes et al (40) are concurrent with the results of the European Prospective Investigation into Cancer and Nutrition study performed in 2001 (41), which revealed that SRD5A2 V89L was associated with changes in the serum androgen levels, while another SRD5A2 A49T polymorphism caused a 24% reduction of circulating levels of 3a-diolG in carriers of the GA genotype compared with the GG genotype, leading to a 60% higher risk of developing prostate cancer (24,40).…”

Variants in the SRD5A2 gene are associated with quality of semen

“…Although certain studies have shown an association with prostate disease, the results are conflicting (25)(26)(27). As yet, there are no conclusions on whether V89L mutation is associated with the risk of prostate cancer (15,28), and there is no conclusive evidence of V89L polymorphism affecting serum …”

“…The most common variation is a valine to leucine substitution at codon 89 (V89L, rs523349), which has been associated with prostate cancer. Due to this variation, there is an approximately 30% reduced activity of SRD5A2 in Asian men (13), which is not found in European populations (14)(15). The other missense polymorphism is at codon 49, substituting an alanine with a threonine at codon 49 (A49T).…”