FSHB promoter polymorphism within evolutionary conserved element is associated with serum FSH level in men

Abstract

Background: No polymorphisms affecting serum FSH levels have been described in the human FSHB gene. We have identified a potential regulatory single nucleotide polymorphism (SNP, rs10835638; G/T) 211 bp upstream from the FSHB mRNA transcription start-site, located within a highly conserved region among placental mammals. We aimed to determine the correlation of carrier status of rs10835638 alternative alleles with serum FSH level in men, and testicular and hormonal parameters.

Methods: A quantitative genetic association study using a cohort of healthy men (n = 554; age 19.2 +/- 1.7 years) visiting the Centre of Andrology, Tartu University Hospital, Estonia.

Results: Rs10835638 (allele frequencies: G 87.6%, T 12.4%) was significantly associated with serum FSH level (analysis of variance: F = 13.0, P = 0.0016, df = 1; regression testing for a linear trend: P = 0.0003). Subjects with the GG genotype exhibited higher FSH levels (3.37 +/- 1.79 IU/l, n = 423) compared with heterozygotes (2.84 +/- 1.54 IU/l, n = 125) (P = 0.0005), the group of T-allele carriers (GT+TT, 2.78 +/- 1.51 IU/l, n = 131) (P = 0.0005) and TT-homozygotes (2.02 +/- 0.81 IU/L, n = 6) (P = 0.031). Rs10835638 was also associated with significant (P < 0.05) reduction in free testosterone index and testes volume, but increased semen volume, sex hormone-binding globulin, serum testosterone and estradiol. LH and inhibin-B levels did not differ significantly between groups.

Conclusions: The identification of a regulatory SNP in FSHB promoter paves the way to study the effect of constitutively low FSH on male health and fertility. As FSH contributes to follicular development and sex steroid production in women, the role of this FSHB variant in female reproductive success is still to be addressed.

Figure 1:

Location of rs10835638 (G/T) (a) within the human FSHB genomic region and (b) on the comparative alignment of the conserved 5′ upstream sequence element shown to act as PRE in ovine Fshb promoter (Webster et al., 1995). Black and white boxes indicate coding and non-coding exons E1–E3, respectively. The location of the rs10835638 (position −211) and the PRE element (from −212 to −197) is shown relative to transcription start-site of the human FSHB gene. The ovine PRE element (Webster et al., 1995) is indicated on the alignment as the boxed sequence and the nucleotide G corresponding to the position of the human polymorphism G/T is highlighted with larger font. Ovis aries, domestic sheep; Homo sapiens, human; Macaca mulatta, rhesus monkey; Mus musculus, house mouse; Canis lupus, dog; Dasypus novemcinctus, Nine-banded Armadillo.

Figure 2:

Boxblots for the distribution of (a) serum FSH, (b) free androgen index, (c) Inhibin-B, (d) LH, (e) combined testicular volume (left + right), (f) sperm concentration, (g) testosterone and (h) estradiol in study subjects subgrouped according to their FSHB promoter SNP rs10835638 genotype, either as GG (n = 423), GT (n = 125) or TT (n = 6) individuals. The boxes represent the 25th and 75th percentiles; whiskers are lines extending from each end of the box covering the extent of the data on 1.5× inter-quartile range. The median value is denoted as the line that bisects the boxes. Circles represent the outlier values. For each boxplot are shown P-values of Marker–Parameter association analysis: one-way ANOVA and regression testing for a linear trend.