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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.

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We investigated the association of endothelial nitric oxide synthase (NOS3) polymorphisms rs2070744 (-786T> C), 27-bp repeat 4b/4a, rs1799983 (Glu298Asp), rs3918188 (-734C> A), and rs743507 (113G> A) with idiopathic recurrent miscarriage (IRM). This was a case-control study involving women with confirmed IRM (n = 296), and 305 age- and ethnically matched control women. NOS3 rs2070744, rs1799983, rs3918188, and rs743507 genotyping was done by TaqMan assays; NOS3 4b/4a genotyping was done by PCR-ASA. A higher frequency of -786C and 298Asp alleles was seen in IRM cases, which remained associated independently with IRM on multivariate analysis. Allele and genotype distribution of 4b/4a, rs3918188 (-734C> A) and rs743507 (113A> G) were comparable between IRM cases and control women. Taking homozygous wild-type genotype as a reference, regression analysis confirmed the association of Glu298Asp and -786T/C, and rs743507 homozygous carriers with IRM risk. Marked linkage disequilibrium was seen between tested NOS3 variants, thus allowing the construction of 5-locus [-786T> C/4b4a/Glu298Asp/-734C> A/113G> A] haplotypes. Taking the common T4bGCA haplotype as a reference, multivariate analysis confirmed the positive association of C4bTCG haplotype with IRM, after controlling for traditional covariates. Genetic variation at the NOS3 locus represents a genetic risk factor for increased susceptibility to IRM.

We investigated the contribution of JAK2 rs2203724 and STAT3 rs1053023 and rs1053004 to the susceptibility of idiopathic recurrent miscarriage (IRM) in Bahraini (246 cases and 279 controls) and Tunisian (235 cases and 235 controls) Arabs. The distribution of JAK2 rs2203724 and STAT3 rs1053023 genotypes were in Hardy-Weinberg equilibrium (HWE) in both communities, while mild deviation from HWE was noted for rs1053004 in Tunisians but not Bahraini. JAK2 rs2203724 was not associated with IRM in either community, while STAT3 rs1053023 was positively associated with IRM in both Bahraini and Tunisian women. STAT3 rs1053004 displayed mixed association: it was positively associated with IRM in Bahraini (P < 0.001), but not Tunisian women (P = 0.10). Genotype association confirmed the association of both STAT3 variants with IRM under additive, dominant, and recessive models, while the association of STAT3 rs1053023 was seen under additive and dominant, but not recessive models in Tunisians. The contribution of JAK2 and STAT3 variants to IRM susceptibility must be evaluated regarding specific variants, and the ethnic/racial background.