The E211 G>A Androgen Receptor Polymorphism Is Associated with a Decreased Risk of Metastatic Prostate Cancer and Androgenetic Alopecia

Abstract

The androgen receptor (AR) gene encodes a transcription factor, which mediates androgen action in target tissues, including the prostate. Prostate cancer is androgen dependent, implicating AR in susceptibility to this male condition. Male pattern balding, androgenetic alopecia, has recently been associated with prostate cancer, suggesting shared androgen pathways. The CAG and GGC repeats in the AR have been studied extensively as markers of prostate cancer susceptibility, with inconclusive findings, whereas the AR-E211 G>A polymorphism has been associated with androgenetic alopecia. We assessed the repeat linked single nucleotide polymorphism as a marker of risk association in prostate cancer, including androgenetic alopecia, in an Australian population-based case-control study. In 815 prostate cancer cases and 719 controls, the proportion of A-allele carriers was the same in each group. Overall, there was no evidence for an association between the A allele and risk of prostate cancer, however, the proportion of A-allele carriers in metastatic prostate cancer (5%) was lower than in less advanced disease (16%, P = 0.03). The proportion of A-allele carriers was 24% in nonbald men but it was lower in men with vertex alopecia alone (13%, P = 0.001) or in combination with frontal alopecia (7%, P < 0.0001). This inverse association between the A allele and baldness was independent of prostate cancer status (P for interaction = 0.2). These results suggest that the AR-E211 A allele, in linkage with the functional repeat sequences, is associated with a lower risk of metastatic prostate cancer and a lower risk of alopecia.

Androgen Receptor Polymorphism-Dependent Variation in Prostate-Specific Antigen Concentrations of European Men

“…Our finding is in agreement with two previous studies, which reported lower risk of metastatic prostate cancer (19) and an overall decreased risk of prostate cancer (34) in men with the rs6152 A-allele, which is strongly linked with the A-allele of the SNP used in current study. Other studies did not find this association with prostate cancer (35,36), but these study populations were of multiethnic origin, which may have blurred the results.…”

“…One synonymous variant, E213 (rs6152G>A), is located between the two polymorphic CAG and GGN tracts. This variant has been linked to androgenetic alopecia in Caucasian populations, where the minor allele (rs6152A) in these populations was associated with a decreased risk (18)(19)(20). In a previous EMAS analysis, carriers of the rs6152A variant were also found to have significantly lower estradiol levels than those with rs6152G (21).…”

Molecular basis of androgenetic alopecia: From androgen to paracrine mediators through dermal papilla

“…Additionally, AR is highly expressed in dermal papilla cells from beard, another site containing androgen-sensitive hair follicles, based on immunostaining [20] and RT-PCR [10]. From genetic aspects, genetic variability in a 1 Mb region within and centomeric to AR is reportedly associated with AGA at a significant level [23] and E211 G > A AR polymorphism is found to be associated with a decreased risk of AGA [24].…”

Fine mapping of the human AR/EDA2R locus in androgenetic alopecia

“…1). The tag SNP selection procedure was 'forced' to include the following additional SNPs on the basis of (i) the previous association findings of our own or other groups, or (ii) their location in coding regions of the AR and EDA2R genes: rs2497938, 7 rs12396249, 7 rs1041668, 7 rs6152, [2][3][4]8 rs1352015, 5 rs4827545, 5 rs1385699, 5 rs12558842 5 and rs9332971. We selected the polymorphic GGN repeat reported by Hillmer et al 3 as an additional marker to clarify its role in the pathology of AGA.…”