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Association of the Polycystic Ovary Syndrome with Genomic Variants Related to Insulin Resistance, Type 2 Diabetes Mellitus, and Obesity

Departments of Molecular Genetics (J.L.S.M.) and Endocrinology (H.F.E.-M., G.V., J.S.), Hospital Ramón y Cajal, 28034 Madrid, Spain; and Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid (M.C., B.P.), 28029 Madrid, Spain

Address all correspondence and requests for reprints to: Héctor F. Escobar-Morreale, M.D., Ph.D., Department of Endocrinology, Hospital Ramón y Cajal, Carretera de Colmenar km. 9100, 28034 Madrid, Spain. E-mail: hescobarm.hrc{at}salud.madrid.org.

We have evaluated the possible association of polycystic ovary syndrome (PCOS) with 15 genomic variants previously described to influence insulin resistance, obesity, and/or type 2 diabetes mellitus.

Seventy-two PCOS patients and 42 healthy controls were genotyped for 15 variants in the genes encoding for paraoxonase (three variants), plasma cell differentiation antigen glycoprotein, human sorbin and SH3 domain containing 1, plasminogen activator inhibitor-1, peroxisome proliferator-activated receptor-2, protein tyrosine phosphatase 1B (two variants), adiponectin (two variants), IGF1, IGF2, IGF1 receptor, and IGF2 receptor.

Compared with controls, PCOS patients were more frequently homozygous for the –108T variant in paraoxonase (36.6% vs. 9.5%; P = 0.002) and homozygous for G alleles of the ApaI variant in IGF2 (62.9% vs. 38.1%; P = 0.018). Paraoxonase is a serum antioxidant enzyme and, because –108T alleles result in decreased paraoxonase expression, this increase in oxidative stress might result in insulin resistance. G alleles of the ApaI variant in IGF2 may increase IGF2 expression, and IGF2 stimulates adrenal and ovarian androgen secretion.

In conclusion, the paraoxonase –108 CT variant and the ApaI polymorphism in the IGF2 gene are associated with PCOS and might contribute to increased oxidative stress, insulin resistance, and hyperandrogenism in this prevalent disorder.

This work was supported by grants from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Spain (FIS 00/0414, 02/0741, and 02/0578 and RGDM G03/212) and from the Consejería de Educación, Comunidad de Madrid, Spain (CAM 08.6/0024/2000 and 08.6/0010/2001).

Results from this work were presented at the 85th Annual Meeting of The Endocrine Society, Philadelphia, PA, June 2003.

Abbreviations: BMI, Body mass index; IGF1R, IGF1 receptor; PAI-1, plasminogen activator inhibitor-1; PC-1, plasma cell differentiation antigen glycoprotein; PCOS, polycystic ovary syndrome; PON1, paraoxonase; PPAR-2, peroxisome proliferator-activated receptor-2; PTP1B, protein tyrosine phosphatase 1B; SORBS1, human sorbin and SH3 domain containing 1.

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