Busch Alexander S, Hagen Casper P, Main Katharina M, Pereira Anita, Corvalan Camila, Almstrup Kristian, Mericq Veronica, Juul Anders
Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
J Clin Endocrinol Metab. 2017 May 1;102(5):1740-1749. doi: 10.1210/jc.2016-4013.
Although genetic factors play a pivotal role in male pubertal timing, genome-wide association studies have identified only a few loci. Genetic variation of follicle-stimulating hormone (FSH) action affects adult reproductive parameters and female pubertal timing.
To investigate whether genetic variation affecting FSH action is associated with onset of puberty in boys.
Cross-sectional and longitudinal study of two cohorts of healthy boys.
This was a population-based study.
Danish (n = 1130) and Chilean (n = 424) boys were followed through puberty and genotyped for FSHB c.-211G>T, FSHR c.-29A>G, and FSHR c.2039G>A.
Clinical pubertal staging including orchidometry, anthropometry, and serum gonadotropin levels.
Although the cohorts differed markedly (e.g., body composition and genotype frequencies), genetic variation affecting FSH production (FSHB c.-211G>T) was associated with age at pubertal onset, as assessed by testicular enlargement, in both cohorts. The effect appeared further modified by coexistence of genetic variation affecting FSH sensitivity (FSHR c.-29G>A): After correcting for body mass index (BMI), boys with a ligand-receptor variant combination resulting in weak FSH action (i.e., FSHB c.-211GT/TT and FSHR c.-29AA) entered puberty 0.64 years [95% confidence interval (CI), 0.12 to 1.17 years; Denmark] and 0.94 years (95% CI, 0.00 to 1.88 years; Chile) later than boys with the most effective FSH action. Effects explained 1.7% (Denmark) and 1.5% (Chile) of the variance. In addition, BMI z score was negatively associated with pubertal timing (β = -0.35 years in both cohorts), explaining 17.2% (Denmark) and 7.2% (Chile) of the variance.
In two ethnically distinct populations, we independently identified an association of two genetic loci with male pubertal timing.
尽管遗传因素在男性青春期启动时间方面起着关键作用，但全基因组关联研究仅鉴定出少数几个基因座。促卵泡生成素（FSH）作用的遗传变异会影响成年后的生殖参数以及女性青春期启动时间。
研究影响FSH作用的遗传变异是否与男孩青春期开始有关。
对两组健康男孩进行横断面和纵向研究。
这是一项基于人群的研究。
丹麦（n = 1130）和智利（n = 424）男孩在青春期全程接受跟踪，并对FSHB基因c.-211G>T、FSHR基因c.-29A>G和FSHR基因c.2039G>A进行基因分型。
临床青春期分期，包括睾丸测量、人体测量学和血清促性腺激素水平。
尽管两组人群存在显著差异（如身体组成和基因型频率），但在两组中，影响FSH产生的遗传变异（FSHB基因c.-211G>T）与青春期开始年龄相关，以睾丸增大来评估。影响似乎因影响FSH敏感性的遗传变异（FSHR基因c.-29G>A）的共存而进一步改变：在校正体重指数（BMI）后，配体-受体变异组合导致FSH作用较弱的男孩（即FSHB基因c.-211GT/TT和FSHR基因c.-29AA）比FSH作用最有效的男孩进入青春期的时间晚0.64年[95%置信区间（CI），0.12至1.17年；丹麦]和0.94年（95%CI，0.00至1.88年；智利）。这些影响分别解释了丹麦人群中1.7%和智利人群中1.5%的变异。此外，BMI z评分与青春期时间呈负相关（两组中β均为-0.35年），分别解释了丹麦人群中17.2%和智利人群中7.2%的变异。
在两个种族不同的人群中，我们独立鉴定出两个基因座与男性青春期时间有关联。
