Polycystic Ovary Syndrome - part 6 docx

Genetic Analyses of PCOS 75 In summary, variation in the AR CAG repeat length may be important in the etiology of PCOS, and gradually light is being shed on possible explanations for the contradictory results of previous studies. Further studies in larger cohorts are needed to confirm the importance of variation in the AR to the etiology of PCOS. 4.6. Chromosome 19p13.2 PCOS susceptibility locus (D19S884) We have used family-based test for linkage and association to identify PCOS suscep- tibility genes. In an initial screen of 37 PCOS candidate genes in 150 families, the strongest evidence for association occurred with D19S884 (33). D19S884 is a dinucleotide repeat polymorphism that maps 800 kb centromeric to the insulin receptor (INSR) on chromosome 19p13.2. This marker was originally selected to assess linkage between the PCOS candidate gene, INSR, and PCOS and is located too far from INSR to be considered a suitable marker for association with INSR as 800 kb exceeds the usual distance over which linkage disequilibrium (the biological basis for allelic association) is maintained. It is, therefore, unlikely that this variant is directly associated with genetic variation within the candidate gene INSR itself and that the association that we observe in our families with D19S884 is due to a variant outside of the INSR per se. Further characterization of this region with 18 additional markers and 217 additional families replicated the original findings and found that the strongest evidence for association is still with allele 8 (A8) of D19S884 (94). Secondly, in the complete cohort of 367 families, the region of chr19p13.2 containing D19S884 also has the strongest evidence for linkage to PCOS of any of the 33 candidate gene regions tested in our families (94). We, therefore, concluded that D19S884 or a very closely linked marker is the most likely PCOS susceptibility locus mapping to chromosome 19p13.2. In support of our conclusions are the findings in our data and the HAPMAP and Perlegen data that there is only limited linkage disequilibrium in the vicinity of D19S884 and that D19S884 itself maps directly within a recombination hotspot (http://genome.ucsc.edu). Two relatively small case-control studies have tested for association between D19S884 and PCOS, one of which replicated our results (95) and one which did not (96). Owing to the relatively small size of these studies, it is difficult to evaluate the significance of these findings. D19S884 maps 105 bp 3´ to exon 55 of the fibrillin-3 gene (FBN3), the third member of the fibrillin extracellular matrix protein family, that shows strong sequence homology with fibrillin-1 and -2. Although very little is known about the function of FBN3, the strong sequence homology among members of the fibrillin gene family as well as molecular evidence for fibrillin-1 and -2 suggest that they function in a similar manner (97–101). Because fibrillin-1 and -2 act through the transforming growth factor beta (TGF-)-signaling pathway (97,100,102–106), it follows that FBN3 may do so as well. The TGF--signaling pathway has a wide range of biological actions including tissue differentiation, hormone regulation, cell proliferation, and the development of the immune system (107–110). Multiple members of the TGF--signaling pathway play a role in the biology of the ovary and/or the pathology of PCOS including follistatin, activin, inhibin, and BMP proteins making FBN3 a promising candidate gene for PCOS. The functional role of D19S884 remains to be determined. However, variation in dinucleotide repeat polymorphisms like D19S884 have been shown to play a role 76 Urbanek in both transcriptional (111–119) and splicing enhancer (120–123) activity. Whether D19S884 acts as a distal enhancer element for the INSR (the candidate gene which directed our attention to this area of the genome) or whether it impacts the expression and/or splicing pattern of FBN3 are areas of active research in our laboratory and others. Preliminary evidence indicates that D19S884 and the sequences immediately flanking it have low levels of enhancer activity but that this activity is not correlated with allele status (124). This makes it unlikely that D19S884 is affecting INSR gene expression and more likely that D19S884 has a more direct and localized activity (i.e., within the FBN3). 5. FUTURE DIRECTIONS Although the above described summary of the current state of genetic studies of PCOS may seem rather discouraging, this is not so. We are currently at the brink of a very exciting and potentially extremely rewarding era for the identification of genetic determinants of PCOS due to the convergence of several critical factors. Within the last few years, new reagents and tools have been assembled to make successful analysis of genetically complex disorders eminently feasible. These tools include (1) a nearly complete catalog of common human genetic variation by the HAPMAP project (125,126), (2) efficient and relatively inexpensive high volume genotyping technologies, (3) development of easily accessible analysis software, and (4) most importantly, the assembly of sufficiently large PCOS patient cohorts (48,64,94) to detect genetic variants with effect sizes observed in other complex diseases. When applied to candidate genes, these tools make it possible to fully explore the genetic relevance of these genes to the etiology of PCOS and may help to reconcile some of the discrepant results observed in studies of different variants within the same gene. Finally, it is now possible to carry out WGA studies of PCOS that will identify potentially novel and unexpected genes and variants contributing to the etiology of PCOS. The next 10 years, therefore, promise to be a very exciting and productive era in the genetic analysis of PCOS. REFERENCES 1. 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