First Evidence of Genetic Association Between AKT2 and Polycystic Ovary Syndrome

  1. Mark O. Goodarzi, MD, PHD1234,
  2. Michelle R. Jones, BSC1,
  3. Yii-Der I. Chen, PHD234 and
  4. Ricardo Azziz, MD, MBA, MPH245
  1. 1Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
  2. 2Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California
  3. 3Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California
  4. 4Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
  5. 5Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, California
  1. Corresponding author: Ricardo Azziz, azzizr{at}


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 glycogen synthase kinase 3β (GSK3β). The AKT2 gene was chosen as a candidate for PCOS because its product affects glucose metabolism and mitogenic signaling, interacts with GSK3β, 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, 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.

RESULTS—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).

CONCLUSIONS—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.


  • Published ahead of print at on 3 September.

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    • Accepted August 22, 2008.
    • Received March 13, 2008.
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  1. Diabetes Care vol. 31 no. 12 2284-2287
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