Association of the Polycystic Ovary Syndrome with Genomic Variants Related to Insulin Resistance, Type 2 Diabetes Mellitus, and Obesity
José L. San Millán,
Marta Cortón,
Gemma Villuendas,
José Sancho,
Belén Peral and
Héctor F. Escobar-Morreale
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 ovarysyndrome (PCOS) with 15 genomic variants previously describedto influence insulin resistance, obesity, and/or type 2 diabetesmellitus.
Seventy-two PCOS patients and 42 healthy controls were genotypedfor 15 variants in the genes encoding for paraoxonase (threevariants), plasma cell differentiation antigen glycoprotein,human sorbin and SH3 domain containing 1, plasminogen activatorinhibitor-1, peroxisome proliferator-activated receptor-2, proteintyrosine phosphatase 1B (two variants), adiponectin (two variants),IGF1, IGF2, IGF1 receptor, and IGF2 receptor.
Compared with controls, PCOS patients were more frequently homozygousfor the –108T variant in paraoxonase (36.6% vs. 9.5%;P = 0.002) and homozygous for G alleles of the ApaI variantin IGF2 (62.9% vs. 38.1%; P = 0.018). Paraoxonase is a serumantioxidant enzyme and, because –108T alleles result indecreased paraoxonase expression, this increase in oxidativestress might result in insulin resistance. G alleles of theApaI variant in IGF2 may increase IGF2 expression, and IGF2stimulates adrenal and ovarian androgen secretion.
In conclusion, the paraoxonase –108 CT variant and theApaI polymorphism in the IGF2 gene are associated with PCOSand might contribute to increased oxidative stress, insulinresistance, and hyperandrogenism in this prevalent disorder.
This work was supported by grants from the Fondo de InvestigaciónSanitaria, Instituto de Salud Carlos III, Ministerio de Sanidady Consumo, Spain (FIS 00/0414, 02/0741, and 02/0578 and RGDMG03/212) 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 Meetingof 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 differentiationantigen glycoprotein; PCOS, polycystic ovary syndrome; PON1,paraoxonase; PPAR-2, peroxisome proliferator-activated receptor-2;PTP1B, protein tyrosine phosphatase 1B; SORBS1, human sorbinand SH3 domain containing 1.
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2, protein tyrosine phosphatase 1B (two variants), adiponectin (two variants), IGF1, IGF2, IGF1 receptor, and IGF2 receptor. 
T 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. 
