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Gene Expression Analysis of PCOS Suggests Existence of Subtypes

NEW YORK (GenomeWeb) – An expression- and phenotype-based search for causal variants in polycystic ovarian syndrome (PCOS) suggests that the endocrine condition may encompass multiple subtypes with subtly different genetic contributors.

In an effort to untangle clinical features and patient phenotypes associated with variants that have already been implicated in PCOS risk, researchers from the University of Utah and Massachusetts General Hospital followed more than 400 women with PCOS and 400 unaffected control individuals.

Using detailed phenotyping profiles together with RNA sequencing data generated for a subset of women with PCOS before and after treatment with the drug metformin, the team identified relationships between gene expression, PCOS-associated loci, and phenotypes such as hormone level, metabolic features, and metformin response. Results from the analysis were published in PLOS One yesterday.

"The data suggest potential PCOS subtypes and point to the need for additional studies to replicate these findings and identify personalized diagnosis and treatment options for PCOS," senior author Corrine Welt, an endocrinology, metabolism, and diabetes researcher at the University of Utah, and her co-authors wrote.

More than a dozen genetic variants have been implicated in PCOS risk in women from Han Chinese or European populations, the team explained. But the precise causal variants and their consequences are less well characterized, suggesting new clues about PCOS development and features could stem from studies considering patient genotypes in conjunction with gene expression profiles and phenotypic features.

"We … hypothesized that the relationship between PCOS risk loci and quantitative phenotypic traits would illuminate the underlying PCOS features affected at each locus," the authors wrote. "We also hypothesized that gene expression and associated patterns would identify candidate genes and pathways that could provide insight into the risk mechanism at the loci."

The researchers used the Illumina HumanOmniExpress BeadChip array to genotype 427 women of European ancestry with PCOS and 407 without. The participants underwent physical exams, provided medical histories, and had blood testing to determine their glucose, insulin, lipid, and hormone levels. The team also did intravenous glucose tolerance testing on a subset of the women with PCOS and used Illumina HiSeq 50 instruments to sequence RNA in 10 skin and 33 fat tissue samples from affected women.

By bringing together this phenotypic, genotypic, and expression data with available expression quantitative trait loci information, the team proposed that gonadotropin hormone levels may be linked to expression of the FSHB, FHSR, and LHR genes. On the other hand, results from the analysis suggested that SUMO1P1, KRR1, and other genes may impact PCOS development and traits via effects on metabolic processes, while genes such as GATA4 showed apparent ties to both metabolism and inflammation.

Even so, the researchers saw only a handful cases of PCOS-associated variants that were directly associated with PCOS features. For example, a variant at the FSHB locus was linked to luteinizing hormone levels, they reported, while variants in and around the THADA gene were associated with metformin response.

Likewise, some of the risk variants seemed to influence the expression of PCOS-related genes, while other expression changes appeared to stem from interactions through other upstream gene regulators.

"The expression data point to the importance of growth factors and inflammatory and immune pathways in upstream regulation and effector pathways including reproductive, endocrine, metabolism, and inflammatory pathways," the authors concluded. "The differences in potential upstream regulators and networks affected in the case of each variant point to potentially differing etiologies for PCOS risk at the distinct risk loci."