Almotairi Reema, Mir Rashid, Almasoudi Kholoud S, Husain Eram, Mtiraoui Nabil
Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Prince Fahad Bin Sultan Chair for Biomedical Research, University of Tabuk, Tabuk 71491, Saudi Arabia.
Laboratory of Human Genome and Multifactorial Diseases, Faculty of Pharmacy, University of Monastir, Monastir 5000, Tunisia.
Life (Basel). 2025 Mar 29;15(4):558. doi: 10.3390/life15040558.
As a complicated endocrine condition, polycystic ovarian syndrome affects around 20% of women who are of reproductive age. It is linked to an increased risk of endometrial cancer, cardiovascular diseases, mental illnesses, non-alcoholic fatty liver disease, metabolic syndrome, and Type 2 diabetes. Despite numerous genetic studies identifying several susceptibility loci, these only account for approximately 10% of the hereditary factors contributing to PCOS, leaving its etiology largely unknown. While genome-wide association studies (GWAS) have been conducted on various populations to identify SNPs linked to PCOS risk, no such study has been reported in Tabuk. Thus, this study aims to investigate the association of a glutathione S-transferase M1 (GSTM1) deletion, VEGF gene (I/D) insertion/deletion, and VEGF-2578 gene polymorphism with polycystic ovarian syndrome. In this research study (case-control), we utilized the ARMS-PCR to determine and analyze the polymorphic variants of VEGF-2578 C/A (rs699947). We employed multiplex PCR for the GSTM1 deletion and MS-PCR (mutation specific PCR) for the vascular endothelial growth factor gene insertion/deletion. The findings indicated statistically significant differences in various biochemical and endocrine serum biomarkers, including lipid profiles (cholesterol, HDL, and LDL), Type 2 diabetes markers (HOMA-IR (Homeostatic Model Assessment for Insulin Resistance), free insulin fasting glucose), and hormone levels (testosterone, LH, progesterone and FSH) in PCOS patients. Specifically, regarding the GSTT1 genotype, individuals with the GSTT1-null genotype had an odds ratio (OR) of 4.16 and a relative risk (RR) of 2.14 compared to those with the GSTT1 genotype, with statistically significant differences ( = 0.0001). However, for the GSTM1 genotype, there was a statistically significant difference ( = 0.0002) in the OR and RR for the GSTM1-null genotype, which were 2.66 and 1.64, respectively. Protective effects were observed for individuals with either GSTT1 (+) GSTM1 (-) or GSTT1 (-) GSTM1 (+) genotypes, as well as for those with both null genotypes, yielding an OR of 0.41 and < 0.003. The VEGF rs699947 C>A gene variation showed a statistically significant association between PCOS patients and controls ( < 0.020), with the A allele frequency higher among PCOS patients (0.42 vs. 0.30). Similarly, the VEGF rs4646994 I>D gene variation exhibited a statistically significant difference ( < 0.0034), with the D allele being more frequent in PCOS patients (0.52 vs. 0.35). The VEGF-A allele was strongly linked to PCOS susceptibility in the allelic model, exhibiting an OR of 1.62, RR of 1.27, and < 0.007, while in the allelic comparison, the OR was 1.71, the RR was 1.32, and < 0.004. This study concluded that null genotypes at rs4025935 and rs71748309, an insertion deletion at rs4646994, and the A allele of rs699947 were significantly associated with PCOS predisposition in our population and these could serve as potential loci for PCOS predisposition. To the best of our knowledge, it is the first study to highlight the association between these genetic variations and the predisposition of PCOS in our populations. Large-scale case-control studies in the future are required to confirm these results.
多囊卵巢综合征作为一种复杂的内分泌疾病，影响着约20%的育龄女性。它与子宫内膜癌、心血管疾病、精神疾病、非酒精性脂肪肝病、代谢综合征和2型糖尿病的发病风险增加有关。尽管众多基因研究已确定了几个易感基因座，但这些仅占导致多囊卵巢综合征的遗传因素的约10%，其病因在很大程度上仍不清楚。虽然已在不同人群中开展全基因组关联研究（GWAS）以确定与多囊卵巢综合征风险相关的单核苷酸多态性（SNP），但在塔布克尚未有此类研究报道。因此，本研究旨在调查谷胱甘肽S-转移酶M1（GSTM1）缺失、血管内皮生长因子（VEGF）基因（I/D）插入/缺失以及VEGF - 2578基因多态性与多囊卵巢综合征的关联。在本病例对照研究中，我们利用扩增阻滞突变系统聚合酶链反应（ARMS-PCR）来确定和分析VEGF - 2578 C/A（rs699947）的多态性变体。我们采用多重聚合酶链反应检测GSTM1缺失，采用突变特异性聚合酶链反应（MS-PCR）检测血管内皮生长因子基因插入/缺失。研究结果表明，多囊卵巢综合征患者在各种生化和内分泌血清生物标志物方面存在统计学显著差异，包括血脂谱（胆固醇、高密度脂蛋白和低密度脂蛋白）、2型糖尿病标志物（胰岛素抵抗稳态模型评估（HOMA-IR）、空腹游离胰岛素、空腹血糖）以及激素水平（睾酮、促黄体生成素、孕酮和促卵泡生成素）。具体而言，关于GSTT1基因型，与具有GSTT1基因型的个体相比，GSTT1基因缺失型个体的优势比（OR）为4.16，相对风险（RR）为2.14，差异具有统计学显著性（P = 0.0001）。然而，对于GSTM1基因型，GSTM1基因缺失型的OR和RR分别为2.66和1.64，差异具有统计学显著性（P = 0.0002）。观察到具有GSTT1（+）GSTM1（-）或GSTT1（-）GSTM1（+）基因型的个体以及两种基因均缺失型个体具有保护作用，OR为0.41，P < 0.003。VEGF rs699947 C>A基因变异在多囊卵巢综合征患者与对照组之间显示出统计学显著关联（P < 0.020），多囊卵巢综合征患者中A等位基因频率更高（0.42对0.30）。同样，VEGF rs4646994 I>D基因变异也表现出统计学显著差异（P < 0.0034），多囊卵巢综合征患者中D等位基因更常见（0.52对0.35）。在等位基因模型中，VEGF - A等位基因与多囊卵巢综合征易感性密切相关，OR为1.62，RR为1.27，P < 0.007，而在等位基因比较中，OR为1.71，RR为1.32，P < 0.004。本研究得出结论，rs4025935和rs71748309的基因缺失型、rs4646994的插入缺失以及rs699947的A等位基因与我们研究人群中的多囊卵巢综合征易感性显著相关，这些可作为多囊卵巢综合征易感性的潜在基因座。据我们所知，这是第一项强调这些基因变异与我们人群中多囊卵巢综合征易感性之间关联的研究。未来需要大规模的病例对照研究来证实这些结果。
