Association of Fibrillin‐3 and Transcription Factor‐7‐Like 2 Gene Variants With Metabolic Phenotypes in PCOS

Abstract

Polycystic ovary syndrome (PCOS) is a complex genetic disease characterized by heritable reproductive and metabolic abnormalities. Genetic variants associated with the reproductive phenotype have been mapped to the fibrillin-3 (FBN3) gene and to a novel transcription factor-7-like 2 (TCF7L2) locus (rs11196236 G). The association of these genetic variants with metabolic phenotypes was investigated in 31 PCOS and 18 control women of European ancestry. The insulinogenic index during an oral glucose tolerance test (I30/G30) and insulin secretion rates at the maximal dose during a graded-glucose infusion (ISRmax) were used as indices of insulin secretion. Endogenous glucose production (EGP) and insulin sensitivity (M/I) were determined during a euglycemic clamp. The disposition index (DI) was calculated using M/I and I30/G30 or ISRmax. Compared with noncarriers (n=10) and control (n=10), M/I was decreased (P=1.1 × 10−5) in heterozygous and homozygous PCOS carriers (n=14) of rs11196236 G and this variant predicted M/I (partial r2=0.34, P=0.005) in a regression analysis. Post-absorptive EGP tended to be higher (P=0.040) in heterozygous and homozygous PCOS carriers of the FBN3-associated allele (n=12), allele 8 of D19S884 (FBN3+), compared to PCOS noncarriers (n=19). PCOS carriers of the rs12255372 T (TCF7L2 Caucasian type 2 diabetes mellitus locus) had no significant associated metabolic phenotypes. We conclude that rs11196236 G TCF7L2 variant is associated with peripheral insulin resistance in PCOS but this effect is not seen in control women. The FBN3 risk allele may be associated with changes in basal glucose homeostasis in PCOS. These findings require replication in additional PCOS cohorts.

Polymorphisms of TCF7L2 gene in South Brazilian women with polycystic ovary syndrome: a cross-sectional study

“…In PCOS women with abnormal glucose tolerance, TCF7L2 polymorphisms were associated with defects in insulin secretion (32). Another study with a small sample of 31 PCOS women has found that SNP rs11196236 was associated with peripheral insulin (15). By contrast, similar to other studies with PCOS populations (14, 33, 34), we did not find an association between insulin resistance and SNPs of the TCF7L2.…”

“…Association studies on the single nucleotide polymorphisms (SNPs) of the TCF7L2 gene in PCOS women have produced controversial data, with some studies showing association between SNPs rs7903146 and rs11196236 with obesity-related traits (14) and peripheral insulin resistance (15) and others reporting no such association (16,17).…”

Nonhuman primate models of polycystic ovary syndrome

“…As TGF-β signaling is currently implicated in the pathogenesis of PCOS in women by genetic epidemiologic evidence (Jones et al, 2007; Raja-Khan et al, 2010; Urbanek et al, 1999, 2007), our EPA monkey data support the potential contributory role of epigenomic perturbation in the etiology of PCOS. In support of this, since a reliable genetic marker for PCOS may be fibrillin-3 (Yalamanchi et al, 2012), a key TGF-β-related signaling element expressed in the human fetal ovary (Hatzirodos et al, 2010) when fetal T exposure most comprehensively induces PCOS-like traits in EPA female monkeys, EPA monkeys may epigenetically mimic PCOS in women. Given dysfunctional TGF-β signaling as a putative genetically-based mechanism for developing PCOS, our findings of altered methylation of TGFβ3, TGFBR1, KRAS, BMP2, TFE3, Runx3 and Hoxc8, complement previous studies implicating TGF-β superfamily members or their regulators in the pathophysiology of PCOS, including AMH, inhibin B, growth differentiation factor 9, activin A, follistatin, and fibrillin-3 (Xu et al, 2011).…”

Exaggerated glucagon responses to hypoglycemia in women with polycystic ovary syndrome

“…Neuroglycopenic symptoms were assessed every 15 min as reported [10]. Arterialized venous blood samples were obtained as reported [15] at −30, −15, and 0-min and every 5-min for the duration of the study. Blood glucose levels were determined in every sample using a YSI Glucose Analyzer (YSI Inc, Yellow Springs, OH).…”

“…Glucose, [6,6 2 H]-glucose specific activity, total and bioavailable T, sex hormone binding globulin, dehydroepiandrosterone sulfate, insulin, C-peptide, epinephrine, and norepinephrine levels were determined as reported [15, 16]. Cortisol and GH assays were performed at the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core on Siemens Immulite 2000 immunoassay system (Siemens Healthcare Diagnostics, LA, CA).…”