Gly972Arg of IRS-1 and Lys121Gln of PC-1 polymorphisms act in opposite way in polycystic ovary syndrome.

PURPOSE: Polycystic ovary syndrome (PCOS) was associated with a number of polymorphisms of genes involved in insulin signaling. So far, they have been studied separately. The aim of this study was to verify the impact of the coexistence of two polymorphisms of insulin signaling. METHODS: One hundred consecutive PCOS women (diagnosed by Rotterdam criteria) and 45 age-matched healthy women were genotyped for two polymorphisms: Gly972Arg of IRS-1 and Lys121Gln of PC-1. Also, they underwent clinical evaluation, blood sampling for measurement of metabolic and hormonal indices, and a 75-g oral glucose tolerance test (OGTT). RESULTS: Comparing PCOS women with controls, the rate of homo-/heterozygosity was significantly greater (50 vs. 24.5%, P = 0.004) for IRS-1 polymorphism, but insignificantly greater (20 vs. 13.3%, P = 0.33) for PC-1 polymorphism. In PCOS women, compared with controls, the genotypes IRS-1 hetero/PC-1 wild type (WT) (36 vs. 17.8%, P = 0.03) and IRS-1 hetero/PC-1 hetero (14 vs. 6.7%, P = 0.20) were overrepresented at the expense of IRS-1 WT/PC-1 WT (44 vs. 68.8%, P = 0.005), while IRS-1 WT/PC-1 hetero was similarly represented (6 vs. 6.7%). Based on genotype, metabolic and hormonal indices changed significantly. For instance, six indices (HOMA-IR, fasting insulin, insulin area under the curve at OGTT, triglycerides, total and calculated free testosterone) were the highest in IRS-1 hetero/PC-1 WT women. CONCLUSIONS: Genetic variations in insulin signaling contribute to the extent and the variability of metabolic and hormonal derangement.

Very high frequency of the polymorphism for the insulin receptor substrate 1 (IRS-1) at codon 972 (glycine972arginine) in Southern Italian women with polycystic ovary syndrome.

A major component of the polycystic ovary syndrome (PCOS) is the insulin resistance. Only a few studies have evaluated the IRS-1 polymorphism at codon 972, sometimes in the absence of a control group, and with great variability in frequency (0-23% in PCOS vs. 0-17% in controls), and with no unequivocal relationships between the polymorphism and clinical or biochemical indexes. The aim of the work was to evaluate the frequency of the IRS-1 polymorphism at codon 972 in PCOS, and correlate it to clinical and biochemical indexes. We assessed the rs 1801278 polymorphic variant in the IRS-1 gene (Gly972Gly=wild-type; Gly972Arg=heterozygosity; Arg972Arg=homozygosity) in genomic DNA by restriction fragment length polymorphism. The study was conducted at an academic medical center with the participation of 65 women with PCOS and 27 age-matched healthy women (controls). Compared to controls, Gly972Arg was very frequent in PCOS (77% vs. 18%, p<0.0001); one PCOS woman was homozygous. Compared to wild-type PCOS, heterozygous PCOS women had only three significantly different indexes: higher fasting insulin, insulin resistance index, and lower 120 min OGTT glucose. Moreover, in the correlation analysis between any two clinical or biochemical variables, the Pearson's correlation coefficients were frequently of different magnitude in heterozygous PCOS versus wild-type PCOS. Overall, heterozygous PCOS had a greater number of statistically significant relationships between different clinical, metabolic and hormonal indexes: 44 direct and 9 inverse versus 6 and 3, respectively. The IRS-1 Gly972Arg has the highest frequency reported world-wide for PCOS women. This variant is associated with insulin resistance and higher fasting insulin in PCOS women.