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Identification of a Polycystic Ovary Syndrome Susceptibility Variant in Fibrillin-3 and Association With a Metabolic Phenotype

Urbanek, Margrit; Sam, Susan; Legro, Richard S.; Dunaif, Andrea

Obstetrical & Gynecological Survey: May 2008 - Volume 63 - Issue 5 - p 311-312
doi: 10.1097/01.ogx.0000312155.17603.54
Gynecology: Genetics

Polycystic ovary syndrome (PCOS), the commonest endocrine disorder affecting women of reproductive age, is associated with metabolic abnormalities including insulin resistance and an increased risk of diabetes. Heritability studies suggest that there is a strong genetic susceptibility to PCOS, and the investigators have mapped a PCOS susceptibility locus to chromosome 19p13.2 near the dinucleotide repeat marker D19S884.

This study was an attempt to localize the susceptibility site and determine its effect—if any —on the metabolic features of PCOS. Resequencing and family-based association testing were used to examine the effect of sequence variation within 100 kb of D19S884 on the reproductive and metabolic phenotypes of PCOS. Genetic analysis was carried out on DNA from 1723 persons in 412 index families with the same number of index cases, and also in 43 affected sisters of predominantly European origin. Genotype/phenotype associations were evaluated in 601 women with PCOS and 168 brothers of affected women.

Of the 53 variants tested, D19S884 allele 8 (A8) within intron 55 of the fibrillin-3 (FBN3) gene was most strongly associated with PCOS. A8 was associated with higher levels of fasting insulin and insulin resistance in women with PCOS, and with higher fasting levels of proinsulin and the proinsulin/insulin ratio in brothers of women having PCOS. A8 was not associated with any particular metabolic profile in unaffected sisters. Patients who were A8-positive did not differ substantially from those who were A8-negative with respect to age, body mass index, waist circumference, or blood pressure.

These findings strongly support the view that A8 of D19S884 is the chromosome 19p13.2 PCOS susceptibility locus, and it seems likely that the same variant contributes to the reproductive and metabolic abnormalities of PCOS in affected women and their brothers.

Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania

J Clin Endocrinol Metab 2007;92:4191–4198

© 2008 Lippincott Williams & Wilkins, Inc.