The 5α-Reductase Type II A49T and V89L High-Activity Allelic Variants are More Common in Men with Prostate Cancer Compared with the General Population

Giwercman, Yvonne Lundberg; Abrahamsson, Per‐Anders; Giwercman, Aleksander; Gadaleanu, Virgil; Ahlgren, Göran

doi:10.1016/j.eururo.2005.06.011

Cited by 33 publications

(24 citation statements)

References 24 publications

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“…[27][28][29][30] In our study, we confirm a lack of association between V89L and risk of prostate cancer. The metaanalysis could not exclude the possibility of an association between the A49T polymorphism and risk of prostate cancer, as confirmed in our study.…”

Section: Discussionsupporting

confidence: 74%

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

Hayes

Severi

Padilla

et al. 2006

Intl Journal of Cancer

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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...

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Section: Discussionsupporting

confidence: 74%

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

Hayes

Severi

Padilla

et al. 2006

Intl Journal of Cancer

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“…Controversies remain regarding the association of this polymorphism with the risk of prostate cancer. Studies have reported a decreased risk of prostate cancer associated with the LL genotype (26,27), an increased risk with the LL genotype (28,29) or no association with risk and this genotype (17,30).…”

Section: Introductionmentioning

confidence: 99%

Polymorphism of the SRD5A2 gene and the risk of prostate cancer

Dusenka

Tomaskin

Kliment

et al. 2014

Molecular Medicine Reports

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Abstract. Androgens are actively involved in the development of the prostate gland and appear to be essential for prostate carcinogenesis. The product of the SRD5A2 gene, membrane-bound steroid 5-α-reductase, type II enzyme, is key in testosterone metabolism. The present study explored the association between the SRD5A2 V89L gene polymorphism and the risk of developing prostate cancer. The study cohort consisted of 456 male Slovak patients, including 260 cases with histologically confirmed prostate cancer and 196 age-matched controls without any clinically suspected infections of the prostate. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to detect the SRD5A2 polymorphism on codon 89. Odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) for different allele variants were calculated in order to determine the association between the SRD5A2 V89L gene polymorphism and prostate cancer. The distribution of V89L variants in the control group was consistent with the Hardy-Weinberg equilibrium (χ 2 test, P=0.266) with a significant deviation in the case group (χ 2 test, P=0.04). However, no association between the SRD5A2 polymorphism and an increased risk of developing prostate cancer was identified. When the wild type VV variant was used as a reference, the ORs for different allele variants ranged from 1.11 (95% CI 0.66-1.87, P=0.70) for the LL genotype to 0.99 (95% CI 0.68-1.46, P=0.99) for the LL + VL genotypes. No particular allele variant was identified to exhibit an increased capacity to promote the development of highly aggressive prostate cancer (Gleason ≥7) or induce carcinogenesis at an earlier onset (<65 years of age). It was confirmed that in the population studied, the SRD5A2 V89L polymorphism was not associated with the risk of prostate cancer and SRD5A2 was not shown to be a key gene involved in prostate cancer development. Published data indicate that a combination of multiple genetic changes are required for prostate cancer development, rather than a single gene change. Therefore, it was hypothesized that high-throughput genotyping may be more effective than single nucleotide polymorphism detection.

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“…The enzymatic activity of SRD5A is highly modulated by single-nucleotide polymorphisms (SNPs) located in these genes (Giwercman et al 2005;Cussenot et al 2007). These genetic variations in key genes belonging to the androgen pathway seem to be important for the prostate response to androgens (Lindstrom et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Intraethnic variation in steroid-5-alpha-reductase polymorphisms in prostate cancer patients: a potential factor implicated in 5-alpha-reductase inhibitor treatment

Henríquez-Hernández

Valenciano

Arnalot

et al. 2015

J Genet

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The 5α-Reductase Type II A49T and V89L High-Activity Allelic Variants are More Common in Men with Prostate Cancer Compared with the General Population

Cited by 33 publications

References 24 publications

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

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

Polymorphism of the SRD5A2 gene and the risk of prostate cancer

Intraethnic variation in steroid-5-alpha-reductase polymorphisms in prostate cancer patients: a potential factor implicated in 5-alpha-reductase inhibitor treatment

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