Common Variants in the Sex Hormone-Binding Globulin (SHBG) Gene Influence SHBG Levels in Women with Polycystic Ovary Syndrome.

BACKGROUND: Decreased sex hormone-binding globulin (SHBG) levels were associated with polycystic ovary syndrome (PCOS). SHBG polymorphisms associated with reduced SHBG production were tested for their association with PCOS, but with inconclusive results. We tested whether altered SHBG levels and SHBG variants were associated with PCOS. METHODS: The study subjects included 242 women with PCOS and 238 control women. SHBG genotyping was done by real-time PCR. RESULTS: Higher minor allele frequency of rs13894, rs858521 and rs727428 was seen in PCOS cases, and significant differences in rs858521 and rs727428 genotypes distribution were seen between PCOS cases and controls. Multivariate regression analysis confirmed the association of only rs727428 with PCOS. Though it was not statistically significant, serum SHBG levels were reduced according to rs727428 genotypes in PCOS cases than in controls. Carriage of rs727428 minor allele was associated with significant increases in free/bioactive testosterone in PCOS cases. Seven-locus (rs9898876-rs13894-rs858521-rs1799941-rs6257-rs6259-rs727428) haploview analysis showed increased frequency of GCCGTGA, GTCGTGA and GTCATGG, and reduced frequency of GTCGTGG haplotypes in PCOS cases than in controls, thus conferring disease susceptibility and protective nature to these haplotypes, respectively. CONCLUSION: Specific SHBG variants affecting serum SHBG levels and SHBG haplotypes are associated with PCOS, suggesting the role for SHBG as PCOS candidate gene.

Transcription Factor-7-Like 2 Gene Variants Affect the Metabolic Phenotypes of Polycystic Ovary Syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrinopathy, which shares genetic features with type 2 diabetes mellitus (T2DM). Insofar as transcription factor 7-like 2 (TCF7L2) is consistently replicated T2DM susceptibility locus, this study evaluates whether common TCF7L2 variants are associated with PCOS and related metabolic features. METHODS: The association between TCF7L2 rs4506565, rs7903146, rs12243326, and rs12255372 SNPs and PCOS was tested in 242 women with PCOS and in 236 control women. RESULTS: The allelic distribution of rs4506565, rs7903146, rs12243326, and rs12255372 TCF7L2 variants was not significantly different between women with PCOS and control women. The genotype distribution of the 4 TCF7L2 loci was comparable between PCOS cases and controls, irrespective of the genetic analysis model used (additive, dominant, recessive). Carriage of rs4506565 minor allele correlated with free insulin and homeostasis model assessment of insulin resistance, while the presence of rs12243326 and rs12255372 minor allele correlated with waist changes. Four-locus (rs4506565-rs7903146, rs12243326, and rs12255372) haplotype analysis identified PCOS-susceptible (ACTG) and -protective (TTTG) haplotypes, which remained significant after controlling for multiple comparisons and for key covariates. CONCLUSIONS: Although individual TCF7L2 variants were not associated with the presence of PCOS in Bahraini women, specific TCF7L2 haplotypes were identified, which were both positively and negatively associated with PCOS.

Validity of adiponectin-to-leptin and adiponectin-to-resistin ratios as predictors of polycystic ovary syndrome.

OBJECTIVE: To evaluate the association of changes in adipokine ratios with polycystic ovary syndrome (PCOS) and related features as altered levels of the adipokines adiponectin, leptin, and resistin were linked with the pathogenesis of PCOS. DESIGN: Case-control retrospective study. SETTING: Outpatient obstetrics/gynecology and adult endocrinology clinics. PATIENT(S): Unrelated women with PCOS (n = 211) and age-matched control women (n = 215). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Utility of adiponectin/leptin and adiponectin/resistin ratios as potential biomarkers of PCOS and associated features. RESULT(S): Significant differences in adiponectin but not leptin or resistin serum levels were seen between women with PCOS and control women. Ratios of adiponectin/leptin and adiponectin/resistin, but not leptin/resistin ratios, were statistically significantly different between PCOS cases and control women. Receiver operated characteristics area under the curve demonstrated sensitivity and specificity for adiponectin/leptin and adiponectin/resistin but not leptin/resistin ratios or individual adipokines as predictors of PCOS. Adiponectin/leptin and adiponectin/resistin ratios negatively correlated with body mass index, homeostatic model assessment, insulin resistance, and free insulin, testosterone, and sex hormone-binding globulin. In addition, adiponectin/resistin ratio negatively correlated with menarche. CONCLUSION(S): Ratios of adiponectin/leptin and adiponectin/resistin constitute novel predictor factors to explain PCOS and associated features and thus may present target for novel therapeutics in PCOS.

Leutinizing hormone/choriogonadotropin receptor and follicle stimulating hormone receptor gene variants in polycystic ovary syndrome.

PURPOSE: Previous studies identified follicle-stimulating hormone receptor (FSHR) and luteinizing hormone/choriogonadotropin receptor (LHCGR) genes as polycystic ovary syndrome (PCOS) susceptibility loci, which was dependent on the racial/ethnic background of studied population. We investigated the association of genetic variants in FSHR and LHCGR with PCOS in Bahraini Arab women. METHODS: A retrospective case-control study, involving 203 women with PCOS, and 211 age- and ethnically-matched control women. FSHR and LHCGR genotyping was done by allelic exclusion method (real-time PCR). RESULTS: Significantly lower frequencies of heterozygous LHCGR rs7371084 and FSHR rs11692782 genotype carriers were seen between women with PCOS vs. controls, and increased frequency of heterozygous homozygous LHCGR rs4953616 genotype carriers were detected between women with PCOS compared to control women. Limited linkage disequilibrium was noted among LHCGR and FSHR SNPs, and 2 blocks were constructed: the first (Block 1) spanning 61 kb contained the six tested LHCGR SNPs, and the second (Block 2) spanning 298 kb contained four of the five tested FSHR SNPs. Higher frequency of LHCGR GTCAAG haplotype was seen in women with PCOS compared to controls; the frequencies of the remaining LHCGR haplotypes, and all FSHR haplotypes were similar between cases and controls. CONCLUSION: This is the first study to confirm the association of novel LHCGR (rs7371084, rs4953616) and FSHR (rs11692782) SNPs with PCOS. The differential association of LHCGR and FSHR variants with PCOS confirms the racial/ethnic contribution to their association with PCOS.

DENND1A gene variants in Bahraini Arab women with polycystic ovary syndrome.

Recent genome-wide association studies and replication analyses reported an association between variants of DENND1A gene and polycystic ovary syndrome (PCOS), mostly in Asians. We therefore examined whether the common DENND1A SNPs rs10818854, rs2479106, and rs10986105 are associated with PCOS in Bahraini Arab population. This case-control study involved 191 women with PCOS diagnosed according to the Rotterdam criteria, and 202 control women. SNP genotyping was performed by the allelic discrimination in real-time PCR. The outcome was that the minor allele frequencies of SNPs rs10818854, rs2479106, and rs10986105 were similar between women with PCOS and control women (P>0.05), even before correcting for multiple testing, and none of the tested DENND1A SNPs were associated with PCOS under co-dominant, dominant, or recessive genetic models. None of the tested DENND1A variants were associated with PCOS features (hirsutism, insulin sensitivity, menses pattern, free testosterone, and free androgen index). Taking common GTA haplotype as reference (OR=1.00), [rs10818854/rs2479106/rs10986105] 3-locus haplotype analysis demonstrated lack of association of any of the DENND1A haplotypes with PCOS, even before correcting for multiple testing. To conclude we demonstrated lack of association of DENND1A SNPs rs10818854, rs2479106, and rs10986105, previously associated with PCOS in Asians, with PCOS in Bahraini Arab women.

Poor prognosis in cycles following "genuine" empty follicle syndrome.

OBJECTIVES: The aim of this study was to investigate the prognosis in future IVF cycles of patients with empty follicle syndrome (EFS). STUDY DESIGN: EFS cases and their future cycles were reviewed. Clinical pregnancy rate per started cycle was taken as the primary outcome in assessing the future outcome in IVF treatment cycles. RESULTS: A total of 3023 patients underwent 5238 IVF treatment cycles. Twenty-six patients (1%) had a total of 58 (1%) cycles of EFS. Thirteen women went through 32 further IVF treatment cycles following the diagnosis of EFS, yielding only two clinical pregnancies, giving a clinical pregnancy rate of 6.25% per started cycle. In addition, four patients had recurrence in a total of 15 cycles. CONCLUSIONS: The occurrence of EFS will indicate poor IVF success in subsequent IVF cycles. Patients with "genuine EFS" should be counselled about the outcome of their future IVF cycles.

STAT3 polymorphisms linked with idiopathic recurrent miscarriages.

PROBLEM: We investigated the association of signal transducers and activators of transcription (STAT)3 gene variants with idiopathic recurrent miscarriage (RM). METHOD OF STUDY: A case-control study involving 189 RM patients and 244 control women was carried out. STAT3 (rs1053004 and rs1023023) genotyping was performed by allelic discrimination/real-time PCR method. RESULTS: STAT3 rs1053004 C allele [OR (95% CI) = 1.60 (1.22-2.10)] and C/C genotype [OR (95% CI) = 3.42 (1.70-6.92)] were positively associated with RM. Two-locus (rs1053004/rs1053023) haplotype analysis revealed increased frequency of CG and CA haplotypes in RM patients, of which only CA haplotype (Pc = 0.020) remained positively associated with RM after applying the Bonferroni correction. This was confirmed by multivariate regression analysis (OR = 1.70; 95% CI = 1.17-2.46) after adjusting for a number of covariates. CONCLUSION: STAT3 rs1053004 variant is significantly associated with idiopathic RM. Replication studies on other racial groups and other STAT3 gene variants are warranted.