Small effect of the androgen receptor gene GGN repeat polymorphism on serum testosterone levels in healthy men

Abstract

Objective: The human androgen receptor (AR) contains a polyglutamine and a polyglycine stretch which are highly polymorphic and are coded respectively by a CAG and GGN repeat in exon 1 of the AR gene. Although the in vitro studies indicated a possible effect of the GGN repeat polymorphism on the AR gene transcription and clinical observations suggest that it might modulate the androgen action, its functional significance remains unclear. We wanted to assess whether the GGN repeat affects the serum testosterone levels in healthy men, which is the expected outcome through feedback regulation if it influences androgen action as has been shown to be the case for the CAG repeat. Design and patients: A population based cross-sectional cohort study including 1476 healthy young, middle-aged, and elderly men. Measurement: Testosterone and LH levels were determined by immunoassay; free testosterone (FT) levels were calculated. Genotyping of the GGN repeat was performed using the sequencing technique. Results: The GGN repeat number was significantly associated with circulating testosterone and FT levels (PZ0.017 and PZ0.013 respectively). However, taking into account that age, body mass index, and CAG are already in the regression model, the GGN repeat could explain only a small part of the variation of both testosterone and FT. Conclusion: To our knowledge, this study is the first to demonstrate a significant positive association between the GGN repeat and androgen levels in a large cohort of healthy men. Although the present study thus adds credence to the view that the polyglycine tract in the AR can modulate AR action, this effect appears to be only small so that its clinical relevance remains questionable.

Genetic Variations in the Androgen Receptor Are Associated with Steroid Concentrations and Anthropometrics but Not with Muscle Mass in Healthy Young Men

“…Genetic variations in the AR gene, in particulary CAG repeat polymorphisms, have been associated with disorders linked to a reduced androgen activity [27]. We have previously shown that serum T levels are positively associated with the CAG and GGN repeat length in young, middle-aged and elderly men [9], [13]. This is in contrast with the present study, in which we did not find any correlation between TT or FT and the GGN repeat length.…”

“…Polymorphisms in the AR gene have been described to alter this activity. We have previously shown that diminished androgen feedback, and consequently higher serum T concentrations, are associated with the CAG repeat length, and to a lesser extend with the GGN repeat length [9], [13]. Furthermore, some single nucleotide polymorphisms (SNP) in the AR gene, resulting in an altered binding with cofactors, have been linked with the androgen insensitivity syndrome (AIS) [14]–[16] and could therefore affect androgen action and circulating androgen levels.…”

Androgen receptor gene polymorphisms and maximal fat oxidation in men. A longitudinal study.

“…The non-significant small increase in circulating androgen levels (2.2%) could have also contributed to explaining the lower accumulation of fat mass in the GGN L group. In agreement, greater serum concentration of total testosterone and free testosterone has been reported in GNN L than in the GGN S men (32). This also concurs with the association between free testosterone and MFO, as well as between SHBG and the accumulation of trunk fat per day in this study.…”

Cytogenetic and molecular analysis of infertile Chinese men: karyotypic abnormalities, Y-chromosome microdeletions, and CAG and GGN repeat polymorphisms in the androgen receptor gene

“…In addition, the number of GGN repeats in the controls showed that GGN 23 was the only dominant allele. This was consistent with the previous study by Hsing et al (2000) based on normal urban Shanghai Chinese men, but was not consistent with another group (Bogaert et al, 2009) who found that GGN 23 and 24 alleles were dominant, suggesting that conflicting results may be attributed to varying ethnic background and sample selection criteria.…”