Variation in the androgen receptor

A variable number of CAG repeats in exon 1 of the androgen receptor gene on the X-chromosome, which normally ranges between 9 and 35 encodes for a variable number of glutamine residues in the aminoterminal domain of the receptor and is inversely associated with the transcriptional activity of testosterone-responsive target genes. Abnormal expansion of the CAG repeats beyond the number of 36 leads to Kennedy disease, which is accompanied by signs of hypoandrogenism (see Chapter 2 for details). Within the physiological range of 9 to 35, the number of CAG repeats was shown to be inversely associated with the risk of prostate cancer, benign prostatic hyperplasia, sperm production, and bone density, and depression (Dowsing et al. 1999; Ferro et al. 2002; Seidmann et al. 2001; von Eckardstein et al. 2001; Zitzmann et al. 2001a). With respect to cardiovascular disease it is important to emphasize that the number of CAG repeats is positively correlated with flow-mediated vasoreactivity and HDL-cholesterol levels, body fat mass and serum levels of insulin and leptin (Zitzmann et al. 2001b; 2003). These findings underscore the fact that the physiological function of testosterone is to reduce endothelial-dependent vasodilatation, to lower HDL cholesterol and body fat mass and to increase the sensitivity towards insulin and leptin. Because of the multitude of these opposing pro- and anti-atherogenic actions, it is not surprising that we did not find any significant association of the CAG repeat polymorphism with coronary artery disease (Hersberger etal., unpublished observation). Data ofsimilar genetic association studies on possible associations of the CAG polymorphism with other cardiovascular phenotypes and events such as ventricular mass and ejection fraction, stroke and claudicatio will be useful to estimate the clinical importance of testosterone for these entities.

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