Association of estrogen receptor gene variants (ESR1 and ESR2) with polycystic ovary syndrome in Tunisia.

SNV (single nucleotide variation) in estrogen receptor (ESR1 and ESR2) genes are susceptibility markers for complex diseases, such as cancer, metabolic disorders and women infertility. We explored six widely used SNVs in ESR1 (rs2234693, rs9340799, rs3798577, rs3020314) and ESR2 (rs1256049, rs4986938) in polycystic ovary syndrome (PCOS) in women from Tunisia (n = 254) compared to controls (n = 170). Genotyping was performed by RFLP-PCR or real-time PCR and analyzed in GoldenHelix statistical package. Logistic regression revealed association of rs2234693, rs3798577 and rs3020314 (ESR1) and rs1256049 (ESR2), the association of rs2234693 (C/T) being the strongest with P < 4.81 × 10-6, 2.88 × 10-5 after Bonferroni correction, OR 0.31, 95%CI (0.18-0.53)). Correlations were found with LH, LH/FSH or hyperandrogenism and even more significant with metabolic syndrome (rs9340799) and hyperglycemia (rs3798577). Among 14 haplotypes reconstructed in ESR1gene, four haplotypes (H1 to H4) were associated with PCOS the strongest being that of H1 (P < 0.002) supported by Bonferroni (P < 0.033) and permutation tests (P < 4 x10-4). In haplotype trend regression, concordant correlations were found with insulin resistance (P < 0.033) for H2 and with high blood pressure for H3 (P < 0.048). While these data revealed influential role on metabolic rather and hormonal features of PCOS, the association of rs2234693 was the strongest among all ethnic populations studied thus far giving a new insight on estrogen receptor gene variation in distant North African populations and their role in metabolic alteration of PCOS.

Vascular endothelial growth factor (VEGFA) gene variation in polycystic ovary syndrome in a Tunisian women population.

BACKGROUND: Polycystic ovary syndrome (PCOS) is characterized by the growth of a number of small cysts on the ovaries which leads to sex hormonal imbalance. Women who are affected by this syndrome suffer from irregular menstrual cycles, decline in their fertility, excessive hair growth, obesity, acne and most importantly cardiac function problems. The vascular endothelial growth factor (VEGF) plays a pivotal role in tissue vascularization in general and in the pathogenesis of many diseases. The PCOS was found to be associated with high expression levels of VEGF. In women who undergo assisted reproductive procedures (ART), VEGF was found to be a key mediator of other factors to control ovary angiogenesis. Here, we set out to examine the association of VEGFA gene polymorphism with PCOS and its components in a population of Tunisia women to enhance our understanding of the genetic background leading angiogenesis and vascularization abnormalities in PCOS. METHODS: The association of VEGFA gene with PCOS and its components was examined in a cohort of 268 women from Tunisia involving 118 PCOS patients and 150 controls. VEGFA gene variations were assessed through the analysis of the following SNPs rs699947 (A/C), rs833061 (C/T), rs1570360 (G/A), rs833068 (G/A), rs3025020 (C/T), and rs3025039 (C/T). The linkage disequilibrium between SNPs was assessed using HAPLOVIEW software while combination of SNPs into haplotypes in the population and the reconstruction of the cladogram were carried-out by PHASE and ARLEQUIN programs, respectively. Genetic association and genotype-phenotype correlations were calculated by logistic regression and non-parametric tests (Kruskall-Wallis and Mann-Whitney tests), respectively, using StatView program. RESULTS: We observed 10 haplotypes in our studied cohort whereH1 (ACGG), H2 (ACAG), H7 (CTGG) and H8 (CTGA) were the most frequent. We observed the association of the genotype CT of the SNP rs30225039 with PCOS phenotype (P = 0.03; OR 95 % CI = 2.05 [1.07-3.90]) and a trend for correlation of the pair of haplotypes H2/H2 with prolactin levels in plasma (P = 0.077; 193.5 ± 94.3 vs 45.7 ± 7.2). These data are consistent with literature and highlight one more time the role of vascularization in the pathogeny of PCOS. CONCLUSIONS: LD pattern in VEGF locus showed a similar LD pattern between the Tunisian population and the CEU. More haplotypes in the Tunisian population than in CEU was observed (22 haplotypes vs 16 haplotypes) suggesting higher recombination rate in Tunisians. The study showed that there was any advantage of using haplotypes compared with SNPs taken alone.