Grigorova M, Punab M, Kahre T, Ivandi M, Tõnisson N, Poolamets O, Vihljajev V, Žilaitienė B, Erenpreiss J, Matulevičius V, Laan M
Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
Andrology. 2017 May;5(3):495-504. doi: 10.1111/andr.12344. Epub 2017 Mar 23.
Androgen receptor (AR) is a transcription factor that is activated upon binding to testosterone (T) and is implicated in regulating the expression of reproduction-related genes. The human AR gene (Xq11-12) spans 186,588 bp and eight exons. N-terminal transactivation domain of the encoded AR protein harbours two polymorphic stretches of identical amino acids, a polyglutamine tract (encoded by 8-37 CAG-repeats) and a polyglycine tract (encoded by 10-30 GGN-repeats). We set forward to analyse independent and combinatory effects of the length of these repetitive tracts on male reproductive hormones, testicular and sperm parameters in a population-based cohort of Baltic young men (n = 974; aged 20.1 ± 2.1 years). We designed an assay to amplify and detect simultaneously the variants of both polymorphic repeats. The study revealed that elongated AR CAG tract was associated with lower FSH (linear regression: p = 0.0002, effect per repeat -0.056 IU/L). As a novel finding, the carriers of GGN-stretch with ≥24 repeats showed a trend for decreased sperm concentration (p = 0.027). Although neither of the variants exhibited an isolated effect on circulating T, their allelic combinations modulated serum T levels, as well as sperm concentration. The lowest T was measured for men carrying the AR gene with long CAG (n ≥ 25) and short GGN (n ≤ 21) repeat tracts (mean 18.8 vs. 25.5-28.6 nmol/L for the other AR variants, p = 0.017). The lowest sperm concentration was detected among individuals with both elongated repetitive stretches (CAG, n ≥ 25 and GGN, n ≥ 24; mean 49.0 vs. 68.4-72.1 mill/mL for the other variants; p = 0.00059). The innovative study design enabled to clearly demonstrate a combinatory impact of CAG and GGN repeat lengths at male reproductive parameters. As AR regulates transcription of over 900 genes in many tissues and organs, the combinatory effects of these common repeat-length variants on male physiology in the wider context and across lifetime are still to be assessed.
雄激素受体（AR）是一种转录因子，在与睾酮（T）结合后被激活，并参与调节生殖相关基因的表达。人类AR基因（Xq11 - 12）跨度为186,588 bp，包含8个外显子。编码的AR蛋白的N端反式激活结构域含有两段相同氨基酸的多态性序列，一段是聚谷氨酰胺序列（由8 - 37个CAG重复编码）和一段聚甘氨酸序列（由10 - 30个GGN重复编码）。我们着手分析这些重复序列长度对波罗的海年轻男性群体（n = 974；年龄20.1±2.1岁）的男性生殖激素、睾丸和精子参数的独立及联合影响。我们设计了一种检测方法，可同时扩增和检测这两个多态性重复序列的变体。研究表明，AR基因CAG序列延长与较低的卵泡刺激素水平相关（线性回归：p = 0.0002，每个重复序列的影响为 - 0.056 IU/L）。作为一项新发现，携带≥24个重复序列的GGN序列携带者的精子浓度有降低趋势（p = 0.027）。虽然这两个变体单独对循环中的T均无影响，但它们的等位基因组合可调节血清T水平以及精子浓度。携带长CAG（n≥25）和短GGN（n≤21）重复序列的AR基因男性的T水平最低（平均值为18.8 nmol/L，而其他AR变体为25.5 - 28.6 nmol/L，p = 0.017）。在两个重复序列均延长的个体中检测到最低的精子浓度（CAG，n≥25且GGN，n≥24；平均值为49.0百万/毫升，而其他变体为68.4 - 72.1百万/毫升；p = 0.00059）。这项创新的研究设计能够清楚地证明CAG和GGN重复序列长度对男性生殖参数的联合影响。由于AR在许多组织和器官中调节超过900个基因的转录，这些常见重复序列长度变体对男性生理在更广泛背景下及一生中的联合影响仍有待评估。
