The GGN and CAG repeat polymorphisms in the exon-1 of the androgen receptor gene are, respectively, associated with insulin resistance in men and with dyslipidemia in women

The human androgen receptor (AR) gene possesses two trinucleotide repeats of CAG and GGN in exon-1. The GGN repeat affects the amount of AR protein translated, while the CAG repeat affects the efficiency of AR transcriptionaly. In this study, we have genotyped these polymorphic tracts in a representative sample of 557 Caucasian adult individuals (314 women and 243 men) from the Canary Islands, Spain (the ENCA Study), and investigated their association with fasting serum levels of lipids, glucose and insulin. The number of CAG repeats in women (expressed as the average length of the two alleles) was inversely correlated with serum levels of LDL-cholesterol (Spearman rho = −0.179; P < 0.01). Women with an average number of CAG repeats in the upper tertile showed significantly lower levels of LDL-cholesterol than those grouped in the lower and middle tertile, after adjusting for age, body mass index, waist-to-hip ratio, smoking and alcohol drinking. The number of GGN repeats in men was correlated with fasting insulin levels (Spearman rho = −0.206; P < 0.01), the homeostasis model assessment of insulin resistance (HOMA-IR; Spearman rho = −0.230; P < 0.01) and the McAuley index of insulin sensitivity (Spearman rho = 0.194; P < 0.01). Men with a number of GGN repeats in the upper tertile showed lower levels of insulin and HOMA and a higher level of the McAuley index than those grouped in the lower and middle tertile, after adjusting for the variables listed above. These results support the hypothesis that the longer alleles of the CAG and GGN polymorphisms in the exon-1 of the AR gene, indicative of lower androgenic signaling, respectively protect women from developing dyslipemia and men from developing insulin resistance.