Novel linkage and association of TCF7L2 variants with PCOS in Italian families.

OBJECTIVE: Transcription factor 7-like 2 (TCF7L2) gene variants confer risk for type 2 diabetes and metabolic traits. We investigated the role of TCF7L2-variants in polycystic ovarian syndrome (PCOS), which is a common endocrine metabolic disorder affecting women of reproductive age. We tested whether TCF7L2 variants are in linkage to and/or in linkage disequilibrium [(LD), namely linkage and association)] with PCOS. PATIENTS AND METHODS: Within 212 families from the Italian peninsular population, we analyzed 78 variants using Pseudomarker software for linkage to and LD with PCOS under the dominant model with complete penetrance (D1). In a secondary analysis, we tested the variants under the recessive models with complete penetrance (R1), dominant with incomplete penetrance (D2), and recessive with incomplete penetrance (R2). We tested through in silico analysis the risk variants to detect any potential functional effects. RESULTS: We identified a total of 14 variants in the TCF7L2 gene significantly linked to and/or in LD with the risk of PCOS (p < 0.05) across different models. CONCLUSIONS: This study is the first to report TCF7L2 linkage and linkage disequilibrium in Italian families with PCOS.

Genome-wide linkage and association study identifies novel genes and pathways implicated in polycystic ovarian syndrome.

OBJECTIVE: Polycystic ovarian syndrome (PCOS) is a complex heterogeneous condition that affects women of reproductive age, conferring increased cardiovascular morbidity and mortality. The syndrome is characterized by oligomenorrhea, hyperandrogenism, and/or polycystic ovaries and is often associated with obesity and type 2 diabetes. Individuals are predisposed to PCOS by environmental factors and risk variants in genes mostly involved in ovarian steroidogenesis and/or insulin resistance. Genetic risk factors have been identified by both familial and genome-wide (GW) association studies. However, most genetic components are still unknown and missing heritability needs to be elucidated. To learn more about the genetic determinants of PCOS, we performed a GW study in genetically highly homogeneous peninsular families. PATIENTS AND METHODS: We conducted the first GW-linkage and linkage disequilibrium (i.e., linkage + association) study in Italian families with PCOS. RESULTS: We identified several novel risk variants, genes, and pathways potentially implicated in the pathogenesis of PCOS. Specifically, we detected 79 novel variants with significant GW-linkage and/or -association with PCOS across 4 inheritance models (p < 0.00005), of which 50 variants were within 45 novel PCOS-risk genes. CONCLUSIONS: This is the first GW-linkage and linkage disequilibrium study performed in peninsular Italian families and reporting novel genes in PCOS.

Oxytocin receptor (OXTR) is a risk gene for polycystic ovarian syndrome.

OBJECTIVE: Oxytocin (OXT) controls appetite, promotes diet-induced energy expenditure, and may protect against obesity. Furthermore, the oxytocin system controls ovarian follicle luteinization and steroidogenesis as well as adrenal steroidogenesis, which if impaired might lead to anovulation and hyperandrogenism, signs found in women with polycystic ovarian syndrome (PCOS). PCOS is a common complex endocrine disorder of reproductive-age women, and it often presents with impaired glucose metabolism, insulin resistance (IR), and type 2 diabetes (T2D). The oxytocin receptor gene (OXTR) may confer a risk for PCOS, conceivably through dysregulation of metabolism, ovarian follicle maturation, and ovarian and adrenal steroidogenesis. Therefore, we aimed to investigate whether OXTR variants confer risk for PCOS. SUBJECTS AND METHODS: In 212 Italian subjects with T2D and PCOS, we have analyzed 22 single nucleotide polymorphisms (SNPs) within the OXTR gene for linkage to and/or linkage disequilibrium (LD, i.e., association) with PCOS. We tested whether the significant risk variants were independent or part of an LD block. RESULTS: We found 5 independent variants significantly linked to/in LD with PCOS within the peninsular families. CONCLUSIONS: This is the first study to report OXTR as a novel risk gene in PCOS. Functional and replication studies are needed to confirm these results.

The mineralocorticoid receptor gene (NR3C2) is linked to and associated with polycystic ovarian syndrome in Italian families.

OBJECTIVE: Polycystic ovarian syndrome (PCOS) is a complex heterogeneous disorder characterized by hyperandrogenism, irregular menses, and subfertility and often accompanied by other related comorbid disorders such as insulin resistance, obesity, and type 2 diabetes. Several genetic risk factors predispose to PCOS, but most are still unknown. Up to 30% of women with PCOS may have hyperaldosteronism. Blood pressure and the ratio of blood levels of aldosterone to renin are higher in women with PCOS compared to healthy controls, even if still in the normal range; and the aldosterone antagonist spironolactone has been used as therapy for PCOS, mainly due to its antiandrogenic activity. Thus, we aimed to investigate the potential pathogenetic role of the mineralocorticoid receptor gene (NR3C2) as the encoded NR3C2 product binds aldosterone and plays a role in folliculogenesis, fat metabolism, and insulin resistance. SUBJECTS AND METHODS: Within 212 Italian families with T2D and phenotyped for PCOS, we analyzed 91 single nucleotide polymorphisms in the NR3C2 gene. We tested the NR3C2 variants for linkage and linkage disequilibrium to the PCOS phenotype by using parametric analysis. RESULTS: We found 18 novel risk variants significantly linked to and/or associated with the risk of PCOS. CONCLUSIONS: We are the first to report NR3C2 as a risk gene in PCOS. However, our findings need to be replicated in other ethnic groups in order to reach more solid conclusions.