Which genes have been associated with polycystic ovarian syndrome (PCOS)?

Updated: Sep 19, 2019
  • Author: Richard Scott Lucidi, MD, FACOG; Chief Editor: Richard Scott Lucidi, MD, FACOG  more...
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Wickenheisser et al reported that CYP17 promoter activity was 4-fold greater in cells of patients with PCOS. This research suggests that the pathogenesis of PCOS may be in part related to the gene regulation of CYP17. [21] However, in a study that assessed candidate genes for PCOS using microsatellite markers to look for association in 4 genes— CYP19, CYP17, FST, and INSR —only 1 marker near the INSR gene was found to be significantly associated with PCOS. [22] The authors concluded that a susceptibility locus for PCOS (designated PCOS1) exists in 19p13.3 in the INSR region, but it cannot be concluded that the INSR gene itself is responsible. [22]

Subsequent studies have found additional associations, such as those of 15 regions in 11 genes previously described to influence insulin resistance, obesity, or type 2 diabetes. [23] Individuals with PCOS were found more likely to be homozygous for a variant upstream of the PON1 gene and homozygous for an allele of interest in IGF2. Interestingly, the PON1 gene variant resulted in decreased gene expression, which could increase oxidative stress. The exact result of the IGF2 variant is unclear, but IGF2 stimulates androgen secretion in the ovaries and adrenal glands. [23]

In study by Goodarzi et al, the leucine allele was found to be associated with protection against PCOS, as compared to the valine allele at position 89 in SRD5A2. [24] The leucine allele is associated with a lower enzyme activity. [24] When the results of this study are combined with those of an observational study by Vassiliadi et al, based on urinary steroid profiles in women with PCOS, further support can be found for an important role for 5-alpha reductase in the pathogenesis of this syndrome. [25]

In a genome-wide association study for PCOS in a Han Chinese population, 3 strong regions of association were identified, at 2p16.3, 2p21, and 9q33.3. [26] The polymorphism most strongly associated with PCOS at the 2p16 locus was near several genes involved in proper formation of the testis, as well as a gene that encodes a receptor for luteinizing hormone (LH) and human chorionic gonadotropin (HCG). This polymorphism was also located 211kb upstream from the FSHR gene, which encodes the follicle-stimulating hormone (FSH) receptor. [26]

The polymorphisms most strongly associated with PCOS at the 2q21 locus encode a number of genes, including the THADA gene, which has previously been associated with type 2 diabetes. In addition, 6 significant polymorphisms were identified as being associated with PCOS at the 9q33.3 locus near the DENND1A gene, which interacts with the ERAP1 gene. Elevation in serum ERAP1 has been previously associated with PCOS and obesity. [26]

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