Ben Salem Assila, Megdich Fatma, Kacem Olfa, Souayeh Malek, Hachani Ben Ali Faten, Hizem Sondes, Janhai Faouzi, Ajina Mounir, Abu-Elmagd Muhammad, Assidi Mourad, Al Qahtani Mohammed H, Mahjoub Touhami
Laboratory of Human Genome and multifactorial diseases, LR12ES07, Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia.
University Hospital F. Hached, Unit of Reproductive Medicine, Sousse, Tunisia.
BMC Genomics. 2016 Oct 17;17(Suppl 9):748. doi: 10.1186/s12864-016-3092-5.
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.
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.
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.
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.
多囊卵巢综合征（PCOS）的特征是卵巢上生长多个小囊肿，这会导致性激素失衡。受该综合征影响的女性会出现月经周期不规律、生育能力下降、毛发过度生长、肥胖、痤疮，最重要的是心脏功能问题。血管内皮生长因子（VEGF）在一般组织血管生成以及许多疾病的发病机制中起着关键作用。研究发现PCOS与VEGF的高表达水平相关。在接受辅助生殖程序（ART）的女性中，VEGF被发现是控制卵巢血管生成的其他因素的关键介质。在此，我们着手研究突尼斯女性人群中VEGFA基因多态性与PCOS及其组成成分的关联，以加深我们对导致PCOS血管生成和血管化异常的遗传背景的理解。
在一组来自突尼斯的268名女性中研究VEGFA基因与PCOS及其组成成分的关联，其中包括118名PCOS患者和150名对照。通过分析以下单核苷酸多态性（SNP）rs699947（A/C）、rs833061（C/T）、rs1570360（G/A）、rs833068（G/A）、rs3025020（C/T）和rs3025039（C/T）来评估VEGFA基因变异。使用HAPLOVIEW软件评估SNP之间的连锁不平衡，而通过PHASE和ARLEQUIN程序分别在人群中将SNP组合成单倍型并重建进化树图。分别使用StatView程序通过逻辑回归和非参数检验（Kruskall-Wallis和Mann-Whitney检验）计算遗传关联和基因型-表型相关性。
在我们研究的队列中观察到10种单倍型，其中H1（ACGG）、H2（ACAG）、H7（CTGG）和H8（CTGA）最为常见。我们观察到SNP rs30225039的CT基因型与PCOS表型相关（P = 0.03；OR 95% CI = 2.05 [1.07 - 3.90]），并且单倍型对H2/H2与血浆催乳素水平存在相关趋势（P = 0.077；193.5 ± 94.3 vs 45.7 ± 7.2）。这些数据与文献一致，并再次强调了血管化在PCOS发病机制中的作用。
VEGF基因座的连锁不平衡模式在突尼斯人群和CEU之间显示出相似的连锁不平衡模式。观察到突尼斯人群中的单倍型比CEU中的更多（22种单倍型对16种单倍型），表明突尼斯人的重组率更高。该研究表明，与单独使用SNP相比，使用单倍型没有任何优势。
