The Androgen Receptor Gene

The AR is a member ofthe superfamily of steroid receptors and like most receptors in this family has a DNA binding domain, a hormone binding domain and a transcription modulatory domain which for the AR is completely encoded by the large exon 1 of the AR gene (15). The AR gene maps to the long arm of the X chromosome (15). Within exon 1 are two highly polymorphic tri-nucleotide repeats [a (CAG)n and a (GGC)n]. We became interested initially in the CAG repeat with the recognition that an expansion of that repeat from the normal size range of approximately 8-33 to 36 or greater, was the cause of an uncommon adult onset motor neuron disease, spinal and bulbar muscular atrophy, or Kennedy's disease (16). Men with Kennedy's disease have evidence of hypoandrogenization, including gynecomastia, low sperm counts, and sub-fertility (17). In-vitro studies have demonstrated that ARs with an expanded glutamine tract encoded by this repeat, bind androgens normally but transactivate androgen responsive genes substantially sub-optimally (16). As the expansion ofthis repeat is the sole cause of Kennedy's disease and the apparent sole cause ofthe hypoandrogenization in such men, we hypothesized that there might be altered androgen activity related to the size of the CAG repeat within the normal range of repeats, i.e., that androgen transactivation activity is reduced with increasing number of repeats (18). We further hypothesized that shorter repeats, ifthey are associated with higher androgen transactivation activity, might also be associated with PCA risk. Consistent with this hypothesis, African-American men have the shortest average repeat length, Asians the longest, with whites intermediate, as expected from their respective PCA rates (19).

This hypothesis gained additional credibility when it was shown in transfection assays that transactivation activity is negatively correlated with repeat length within the normal range (20), just as it was in the expanded repeat range seen in Kennedy's disease. We proceeded to explore this hypothesis directly in a small population based case-control study in LA County, in which the case group was comprised ofwhite men under age 65 at PCA diagnosis and the control group was comprised of a comparably aged group of healthy white men from the neighborhoods in which the cases lived at the time ofdiagnosis. We showed in this study that men with CAG repeat length under 20 had a 2.0-fold increase in PCA risk compared to men with a repeat length of 20 or more. This effect was particularly pronounced for advanced disease (OR = 2.36, 95% CI = 1.02, 5.49) (21). This hypothesis has been among the most investigated of all molecular epidemiologic hypotheses of PCA to date (22). Many of these investigations are summarized in Table 1. Not all of these studies are of the same quality, some suffering from low statistical power, others from cases chosen from convenience samples or from controls drawn from non-representative populations. Nonetheless, while there is considerable inconsistency in findings across studies, most find some inverse relationship - either overall, limited to advanced disease or for early onset PCA only - between PCA risk and CAG repeat length.

It is interesting to think about how changes in androgen activity due to incremental changes in CAG repeat length might be expected to alter PCA risk. Cancer rates increase as a logarithmic function of age; for PCA, the most age-related of all cancers, incidence increases by age raised to approximately the 8th power. For most epithelial cancers, including PCA, the relationship between incidence, I, with age, t, can be represented by the equation which produces a straight line of slope k when the logarithm of incidence is plotted against the logarithm of age (39). The fundamental idea is that "aging" of a tissue relates to its cell kinetics, i.e., its effective mitotic rate. When the tissue is not undergoing cell division, the rate of aging is zero, whereas aging is maximal when the mitotic rate is maximal.

Under this model if a single repeat increment results in a 10% increase in androgen activity and, therefore, in prostate tissue "aging," this would translate into potentially as much as a 2.4-fold lifetime increase in PCA risk; a 2% increase would translate into a 20% increase in risk, whereas a 1% increase would translate into a 9% increase, and a 0.5% into a 5% lifetime increase (Table 2).

We have done additional work to understand better mechanistically how CAG repeat length affects androgen activity, and also have begun preliminary studies of how this genetic effect might interact with other genetic variants in the androgen signaling pathway to modify PCA risk. Coetzee, et al. have shown, for example, the importance ofco-activator proteins in realizing the full impact ofCAG repeat length on transactivation activity. His lab has shown that members of the p160 family of co-activator proteins (A1B1 and GRIP1) bind to the region of the poly-glutamine tract encoded by the (CAG)n repeat and that, in-vitro, ligand alone (i.e., DHT) is insufficient for any impact of CAG length on transactivation activity (40). Adding A1B1 or GRIP1 together with DHT not only substantially increases transactivation activity in this system, but also clarifies the substantial impact ofthe length of the poly-glutamine tract on such activity (40). On average, there is approximately a 0.5%-2% decline in activity with each additional poly-glutamine in these in-vitro systems. Based on Table 2, under reasonable assumptions regarding PCA incidence, this would result in a 4% or greater change in lifetime PCA incidence.

Table 1. Summary of Studies Evaluating the Roles of the AR CAG Microsatellite in PCA Risk, Progression, and Age at Onset (22).

Stage/

Age at

Study

Subjects

Risk

Grade

Onset

Pilot studies

N/A1

Irvine, et al. (15)

USA White

yes

N/A

Hardy, et al. (23)

USA White

N/A

no

yes

Ingles, et al. (21)

USA White

yes

yes

N/A

Hakimi, et al. (24)

USA White

yes

yes

no

Matched case-control studies

Giovannucci, et al. (25)

USA White

yes

yes

no

Stanford, et al. (26)

USA White

yes

no

yes

Hsing, et al. (27)

Chinese

yes

no

no

Beilirt, et al. (28)

Australian White

no

no

yes

Other studies

Ekman, et al. (29)

Swedish White

yes

N/A

N/A

Edwards, et al. (30)

British White

no

no

N/A

Correa-Cerro, et al. (31)

French/German

White

no

no

no

Bratt, et al. (32)

Swedish White

no

yes

yes

Lange, et al. (33)

USA White

High Risk

no

no

no

Nam, et al. (34)

Canadian

N/A

yes

N/A

Latil, et al. (35)

French White

no

no

yes

Modugno, et al. (36)

USA White

yes

N/A

N/A

Miller, et al. (37)

USA White

no

N/A

N/A

Panz, et al. (38)

South Africans

Black & White

yes

yes

N/A

1 N/A = Not applicable or not assessed

1 N/A = Not applicable or not assessed

Table 2. Hypothesized Relationship Between Changes in Androgen Activity and Lifetime PCA Risk Resulting from an Incremental Change in CAG repeat Length1.

A in % Androgen Activity

Lifetime Increase in % Incidence

10

114

2

13

Ï

8

0.5

4

1 Based on the following equation: [I (t)

= axt J where I = incidence of PCA at age

(t); k = 8

Although the full set of genes under various conditions that are activated by the AR are still poorly understood, the PSA gene is one whose expression is consistently tied to androgen receptor activity. We have found some evidence that PSA levels are correlated with (CAG)n size in the AR gene. A non-silent SNP (A->G) has been described in the androgen response element ofthe PSA gene (41). We explored preliminarily the relationship of that SNP with PCA risk in conjunction with CAG size in the AR gene. The GG PSA genotype was associated with advanced PCA regardless of AR CAG genotype and CAG genotype was associated with risk regardless of PSA genotype. However, the strongest relationship with PCA risk was for the combined PSA GG, AR CAG short genotypes (OR = 9.6, 95% CI = 2.0, 45.5) (Table 3) (42).

Table 3. PCA Risk, Cross-classified by PSA and AR Genotypes+.

Genotype PSA

Cases <%)

Cases (%)

95% CI Odds Ratio

NotGG

Long1

72 (52)

21 (37)

1.0 (referent)

5(19)

1.0 (referent)

GG

Long1

30 (22)

12(21)

1.4 (0.6-3.1)

9(35)

4.3 (1.3-14.0)

NotGG

Short1

31 (22)

16(28)

(0.8-3.8)

8(31)

3.7 (1.1-12.3)

GG

Short1

6(4)

8(14)

4.6 (1.4-14.7)

4(15)

9.6 (2.0-45.5)

Long = > 20 CAG repeats 2 Short = < 20 CAG repeats

Long = > 20 CAG repeats 2 Short = < 20 CAG repeats

Our research activity related to the AR gene has been useful from several perspectives. It has illustrated the potential importance of focusing on polygenic origins, the critical importance of combining functional studies with epidemiologic analyses in understanding genotype/disease relationships, and the potential for transcribing knowledge gained in understanding the genetic origin ofone disease to understanding others.

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