Association of the (TAAAA)n Repeat Polymorphism in the Sex Hormone-Binding Globulin (SHBG) Gene with Polycystic Ovary Syndrome and Relation to SHBG Serum Levels

Abstract

SHBG levels are frequently low in women with polycystic ovary syndrome (PCOS) and may contribute to increased tissue exposure to free androgens. A (TAAAA)n repeat polymorphism in the promoter of the SHBG gene has been described recently, and its transcriptional activity has been shown to be related to the number of tandem repeats. Recent evidence also suggests that prenatal exposure to androgen excess may program for the development of the PCOS phenotype during adulthood. Our aim was to investigate the possible association of the functional (TAAAA)n polymorphism in the promoter of the SHBG gene with PCOS and its relation to SHBG levels. We studied 185 women with PCOS and 324 normal controls. Genotype analysis revealed six (TAAAA)n alleles containing 6-11 repeats. The distribution of these alleles was different in the two groups. Women with PCOS had a significantly greater frequency of longer (TAAAA)n alleles (more than eight repeats) than normal women who had shorter alleles (less than eight repeats) in higher frequency (P = 0.001). Furthermore, in the PCOS group, carriers of the longer allele genotypes had lower SHBG levels [1.17 +/- 0.68 micro g/dl (35.1 +/- 20.5 nmol/liter)] than those with shorter alleles [1.51 +/- 0.93 microg/dl (45.3 +/- 28 nmol/liter P = 0.02). A novel (TAAAA)n allele, which has not been previously reported, was found in low frequency, mainly in the control population. From these results, there is evidence that there may be a genetic contribution to decreased SHBG levels frequently seen in women with PCOS. The SHBG gene may act as a susceptibility gene for PCOS and may provide the genetic link for the developmental origin hypothesis for PCOS that was recently proposed on the basis of experimental observation in prenatally androgenized sheep and primates.

Low sex hormone-binding globulin as a predictive marker for insulin resistance in women with hyperandrogenic syndrome

“…On the other hand, Bendlova et al reported no significant differences in the genotype distribution between PCOS and controls and no association with plasma SHBG levels (43). Nevertheless, there may be a genetic determination of low SHBG levels contributing to an increase in biologically active androgen levels during fetal, pubertal, and later in life, resulting in different phenotypes of androgen excess (42).…”

“…Some studies have emphasized the influence of genetics on circulating SHBG levels. Recently, it was postulated that polymorphisms within the coding sequence and in the regulatory sequence of the SHBG gene were associated with circulating SHBG levels, which may be a possible genetic background of sex hormone activity in humans (41,42). On the other hand, Bendlova et al reported no significant differences in the genotype distribution between PCOS and controls and no association with plasma SHBG levels (43).…”

Sex hormone-binding globulin gene expression in the liver: Drugs and the metabolic syndrome

“…A c c e p t e d M a n u s c r i p t 6 Moreover, this polymorphism appears to have physiological significance as the number of (TAAAA)n repeats has been associated with the polycystic ovarian syndrome (Xita et al, 2003), age of menarchy (Xita et al, 2005), and bone density in elderly men (Eriksson et al, 2006). (2001) have demonstrated that the transcriptional activity of the SHBG promoter is dependent on the number of (TAAAA)n repeats.…”

Genetic variants of sex hormone-binding globulin and their biological consequences

“…However, other studies in women with PCOS, premenopausal women with hirsutism and in healthy men showed an opposite relation, with carriers of long alleles presenting with lower SHBG concentrations compared to carriers of short alleles. More particularly, in a Greek cohort of women with PCOS it was found that patients with longer repeats (more than eight TAAAA repeats) had lower SHBG levels and higher levels of free androgen index than those with shorter alleles (Xita et al, 2003). This observation was confirmed by Ferk et al (2007), who reported lower serum SHBG levels in women with longer TAAAA alleles not only in PCOS patients but also in healthy women.…”

“…The (TAAAA)n repeat polymorphism has been proposed to act as a susceptibility polymorphism for the development of PCOS (Xita et al, 2003). Women with PCOS were found to have alleles with longer repeats (more than eight TAAAA repeats) more frequently than normal women who had shorter alleles (less than eight TAAAA repeats) in a much higher frequency (Figure 2).…”