Association of the SHBG gene promoter polymorphism with early markers of atherosclerosis in apparently healthy women

Objective: Androgen may be detrimental in the development of cardiovascular disease in women. We investigated possible associations between the (TAAAA)n polymorphism of sex hormone binding globulin (SHBG) gene promoter, which influences transcriptional efficiency of the SHBG gene - and thus the tissue androgen availability - and early markers of atherosclerosis in apparently healthy women.

Design and methods: In this prospective clinical study, 153 consecutive women (mean age 43.9±9 years, 66 of whom postmenopausal, without known diabetes, cardiovascular disease), visiting our internal medicine outpatients were examined for unrecognised features of the metabolic syndrome. Endothelium dependent vasodilatation (FMD) and intima media thickness of the common carotid artery (IMT) were recorded. According to the number of SHBG gene promoter repeats patients were classified as short (≤7), medium (=8) and long repeat (≥9) allele groups.

Results: The (TAAAA)n repeat length was an independent predictor of FMD in multivariate analysis (p<0.03). FMD was positively correlated with SHBG levels (p=0.004). Women carriers of two long alleles had increased IMT (p=0.031) although this was not independent in the multivariate analysis.

Conclusions: Longer (TAAAA)n repeats in the SHBG gene promoter are associated with impaired FMD, which is an early marker of atherosclerosis. As this polymorphism has been associated with a more androgenic phenotype in women, this association may reflect the life-long tissue exposure to higher free androgens and indirectly supports the view that androgenic exposure may have adverse cardiovascular effects in women.