Advanced

Functional characterisation of the CAG polymorphism in the androgen receptor- in vitro and in vivo

Nenonen, Hannah LU (2011) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2011:27.
Abstract
The androgen receptor (AR) is the mediator of androgen actions. In the AR coding region there is a polymorphic CAG repeat encoding a stretch of the amino acid glutamine (Q). The repeat length modulates receptor activity and is normally distributed between 10-30 CAG with a median length of 22 repeats in white men. At the start of this work, a negative linear association between AR function and the CAG repeat number was generally assumed. This assumption was supported by clinical findings in patients with Kennedy’s disease, which is a neuromuscular disorder caused by an abnormally expanded CAG repeat (>40 CAG). However, in vivo data concerning the association between CAG numbers within normal length and androgenic effects were... (More)
The androgen receptor (AR) is the mediator of androgen actions. In the AR coding region there is a polymorphic CAG repeat encoding a stretch of the amino acid glutamine (Q). The repeat length modulates receptor activity and is normally distributed between 10-30 CAG with a median length of 22 repeats in white men. At the start of this work, a negative linear association between AR function and the CAG repeat number was generally assumed. This assumption was supported by clinical findings in patients with Kennedy’s disease, which is a neuromuscular disorder caused by an abnormally expanded CAG repeat (>40 CAG). However, in vivo data concerning the association between CAG numbers within normal length and androgenic effects were conflicting. As understanding the impact of CAG number on the AR activity is important for proper interpretation of this polymorphism and risk of pathological conditions other than Kennedy’s disease, the purpose of this study was to examine the influence of CAG length, if any, on AR activity.

Firstly an in vitro study was performed. A reporter gene with a human androgen responsive promoter was used in a transactivation assay. The repeat lengths included were 16, 22 and 28 CAG, which represent a short, the median, and a long repeat within the normal human range. The study showed that the AR with median repeat length had the highest activity in vitro. Secondly, the effect of the CAG repeat in relation to two androgen dependent conditions, infertility and PCa, was analysed in two separate meta-analyses. When stratifying the CAG repeats into three groups, shorter than median, median and longer than the median CAG length, the meta-analysis on infertile men showed 20% increased risk of infertility in men harbouring other repeat lengths than the most common. On the other hand, CAG number did not have any effect on PCa risk.

The AR regulates the expression of prostate specific antigen (PSA). Thus the expression of PSA can be used as a marker of AR activity in tissue. We measured the AR protein and PSA amount in human prostate tissue from 19 men with known CAG length. Those who were carriers of 22 CAG had lower AR amount and higher PSA than counterparts with other CAG lengths, but this was not statistically significant, probably due to the small study size.

Taken together, these studies indicate that the median length of the androgen receptor CAG repeat is associated with optimal activity, in vitro and in vivo. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Saunders, Philippa, Centre for Reproductive Biology The Queen's Medical Research Institute Edinburgh, Scotland
organization
publishing date
type
Thesis
publication status
published
subject
keywords
androgen receptor, polymorphism, CAG polymorphism, androgen receptor activity, infertility, prostate cancer, androgen receptor function
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2011:27
pages
112 pages
publisher
Department of Clinical Sciences, Lund University
defense location
Jubileumsaulan, Entrance 59, SUS, Malmö
defense date
2011-04-01 09:00
ISSN
1652-8220
ISBN
978-91-86671-75-4
language
English
LU publication?
yes
id
8598fa59-b92c-4039-a9f5-5cee2f6c0dca (old id 1845310)
date added to LUP
2011-03-11 14:13:20
date last changed
2016-09-19 08:44:47
@phdthesis{8598fa59-b92c-4039-a9f5-5cee2f6c0dca,
  abstract     = {The androgen receptor (AR) is the mediator of androgen actions. In the AR coding region there is a polymorphic CAG repeat encoding a stretch of the amino acid glutamine (Q). The repeat length modulates receptor activity and is normally distributed between 10-30 CAG with a median length of 22 repeats in white men. At the start of this work, a negative linear association between AR function and the CAG repeat number was generally assumed. This assumption was supported by clinical findings in patients with Kennedy’s disease, which is a neuromuscular disorder caused by an abnormally expanded CAG repeat (&gt;40 CAG). However, in vivo data concerning the association between CAG numbers within normal length and androgenic effects were conflicting. As understanding the impact of CAG number on the AR activity is important for proper interpretation of this polymorphism and risk of pathological conditions other than Kennedy’s disease, the purpose of this study was to examine the influence of CAG length, if any, on AR activity.<br/><br>
Firstly an in vitro study was performed. A reporter gene with a human androgen responsive promoter was used in a transactivation assay. The repeat lengths included were 16, 22 and 28 CAG, which represent a short, the median, and a long repeat within the normal human range. The study showed that the AR with median repeat length had the highest activity in vitro. Secondly, the effect of the CAG repeat in relation to two androgen dependent conditions, infertility and PCa, was analysed in two separate meta-analyses. When stratifying the CAG repeats into three groups, shorter than median, median and longer than the median CAG length, the meta-analysis on infertile men showed 20% increased risk of infertility in men harbouring other repeat lengths than the most common. On the other hand, CAG number did not have any effect on PCa risk. <br/><br>
The AR regulates the expression of prostate specific antigen (PSA). Thus the expression of PSA can be used as a marker of AR activity in tissue. We measured the AR protein and PSA amount in human prostate tissue from 19 men with known CAG length. Those who were carriers of 22 CAG had lower AR amount and higher PSA than counterparts with other CAG lengths, but this was not statistically significant, probably due to the small study size. <br/><br>
Taken together, these studies indicate that the median length of the androgen receptor CAG repeat is associated with optimal activity, in vitro and in vivo.},
  author       = {Nenonen, Hannah},
  isbn         = {978-91-86671-75-4},
  issn         = {1652-8220},
  keyword      = {androgen receptor,polymorphism,CAG polymorphism,androgen receptor activity,infertility,prostate cancer,androgen receptor function},
  language     = {eng},
  pages        = {112},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Functional characterisation of the CAG polymorphism in the androgen receptor- in vitro and in vivo},
  volume       = {2011:27},
  year         = {2011},
}