AKT2: First Evidence of Genetic Association with Polycystic Ovary Syndrome

Mark O. Goodarzi, MD, PhD, Michelle R. Jones, BSc, Yii-Der I. Chen, PhD and Ricardo Azziz, MD, MBA, MPH
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine (M.O.G., M.R.J.), Department of Obstetrics and Gynecology (M.O.G., Y-D.I.C., R.A.), and Medical Genetics Institute (M.O.G., Y-D.I.C.), Cedars-Sinai Medical Center, Los Angeles, California 90048; and Departments of Medicine (M.O.G., Y-D.I.C., R.A.) and Obstetrics and Gynecology (R.A.), the David Geffen School of Medicine at UCLA, Los Angeles, California 90095
Diabetes Care


Objective: 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 GSK3? . The AKT2 gene was chosen as a candidate for PCOS because its product affects glucose metabolism and mitogenic signaling, interacts with GSK3?, and mediates cell survival in the ovary.

Research Design and Methods: Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; controls were recruited from the surrounding community. 287 White women with PCOS and 187 White controls were genotyped for 4 SNPs in AKT2. Genotyping took place at Cedars-Sinai Medical Center in Los Angeles. Single nucleotide polymorphisms (SNPs) and haplotypes were tested for association with PCOS risk and phenotypic markers of PCOS.

Results: Minor allele carriers of SNPs rs3730051 and rs8100018 had increased odds of PCOS (OR=2.2, p=0.004 and OR=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).

Conclusions: These data suggest that polymorphisms in two components of the insulin signaling pathway, AKT2 and GSK3B, are associated with PCOS. Presence of multiple lesions in a single pathway may confer increased risk.

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