First Evidence of Genetic Association Between AKT2 and Polycystic Ovary Syndrome

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Diabetes care (Impact Factor: 8.42). 10/2008; 31(12):2284-7. DOI: 10.2337/dc08-0532
Source: PubMed


Insulin resistance has been reported in up to 70% of women with polycystic ovary syndrome (PCOS). Physiologic and genetic data currently implicate post-insulin receptor signaling defects in substrates such as glycogen synthase kinase 3beta (GSK3beta). The AKT2 gene was chosen as a candidate for PCOS because its product affects glucose metabolism and mitogenic signaling, interacts with GSK3beta, and mediates cell survival in the ovary.
Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham, and control subjects were recruited from the surrounding community; 287 white women with PCOS and 187 white control subjects were genotyped for four single nucleotide polymorphisms (SNPs) in AKT2. Genotyping took place at Cedars-Sinai Medical Center in Los Angeles. SNPs and haplotypes were tested for association with PCOS risk and phenotypic markers of PCOS.
Minor allele carriers of SNPs rs3730051 and rs8100018 had increased odds of PCOS (odds ratio [OR] 2.2, P = 0.004, and 2.4, P = 0.001, respectively). The haplotype T-G-C-T was significantly associated with PCOS (OR 2.0, P = 0.01). Carriers of the risk haplotypes for both AKT2 and GSK3B had a further increased odds of PCOS (OR 3.1, P = 0.005).
These data suggest that polymorphisms in two components of the insulin signaling pathway, AKT2 and GSK3B, are associated with PCOS. The presence of multiple lesions in a single pathway may confer increased risk.

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    • "In particular, several further observations point to an involvement of insulin receptor (InsR) signaling in PCOS. Defects in InsR phosphorylation (Dunaif et al., 1995) and further genetic lesions in this pathway, affecting InsR, PKBβ (also known as Akt2) and downstream glycogen synthase kinase 3β (GSK3β), are found in individuals with PCOS (George et al., 2004; Tan et al., 2007; Goodarzi et al., 2008; Mukherjee et al., 2009). Insulin can act as a 'co-gonadotrophin' and exogenous administration of LH in rodent models of PCOS can exacerbate PCOS cyst formation (Poretsky et al., 1992). "
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