Department of Biology, Faculty of Science, University of Sistan and Baluchestan, Zahedan, Iran.
Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, 9816743463, Iran.
Biochem Genet. 2023 Oct;61(5):1827-1849. doi: 10.1007/s10528-023-10349-1. Epub 2023 Mar 1.
Polycystic ovarian syndrome (PCOS) is a complex endocrine and metabolic condition with several potential causes. Insulin resistance is a hallmark of PCOS that often coexists with hirsutism, hyperandrogenism, being overweight, and hormonal imbalances. The functioning of multiple replication and transcription factors is regulated by tumor suppressor genes (TSGs), which play a crucial role in maintaining genomic integrity and controlling the cell cycle of granulosa cells. In the present study, we examined how three single nucleotide polymorphisms (SNPs) in TP53, a cell cycle regulatory gene, affect the risk of developing PCOS in a sample of an Iranian population. Genomic DNA was extracted from 200 PCOS patients and 200 healthy women to analyze TP53 rs17880604, rs1625895, and rs1042522 SNPs using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Our findings revealed that the majority of PCOS cases were overweight [25 < body mass index (BMI) < 30]. A positive association was observed between the TP53 rs1042522 SNP and the risk of PCOS under codominant heterozygous and overdominant genetic patterns (odds ratio > 1). Meanwhile, a negative association was observed between TP53 SNPs (rs1625895, rs17880604) and susceptibility to PCOS under codominant heterozygous and dominant models of inheritance (odds ratio < 1). Moreover, different genotype and haplotype combinations of rs17880604/rs1625895/rs1042522 conferred a decreased risk of PCOS in our population. We found no statistical difference in the frequency of TP53 genotypes between PCOS cases and/or controls in terms of BMI, waist circumference, prolactin level, and markers of lipid and carbohydrate profile (P > 0.05). Molecular dynamic prediction showed that the missense substitution in the 17p13.1 position (rs1042522) could change the properties and secondary structure of the p53 protein. As inherited risk factors, TP53 variations may play a pivotal role in the pathogenesis of PCOS among Iranian women. Replicated population-based studies on other ethnicities are required to find the genetic contribution of variants of TP53, or SNPs located in other TSGs, to the etiology of this endocrine disease.
多囊卵巢综合征（PCOS）是一种具有多种潜在病因的复杂内分泌和代谢疾病。胰岛素抵抗是 PCOS 的一个标志特征，常与多毛症、高雄激素血症、超重和激素失衡同时存在。肿瘤抑制基因（TSG）调控着多个复制和转录因子的功能，它们在维持基因组完整性和控制颗粒细胞细胞周期方面起着至关重要的作用。在本研究中，我们研究了细胞周期调节基因 TP53 中的三个单核苷酸多态性（SNP）rs17880604、rs1625895 和 rs1042522 如何影响伊朗人群中 PCOS 的发病风险。我们从 200 名 PCOS 患者和 200 名健康女性中提取基因组 DNA，采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法分析 TP53 rs17880604、rs1625895 和 rs1042522 单核苷酸多态性。我们的研究结果表明，大多数 PCOS 病例为超重患者[25<体重指数（BMI）<30]。TP53 rs1042522 单核苷酸多态性在共显性杂合和超显性遗传模式下与 PCOS 风险呈正相关（优势比>1）。另一方面，TP53 单核苷酸多态性（rs1625895、rs17880604）在共显性杂合和显性遗传模式下与 PCOS 易感性呈负相关（优势比<1）。此外，rs17880604/rs1625895/rs1042522 的不同基因型和单倍型组合降低了我们人群中 PCOS 的发病风险。我们发现，在 BMI、腰围、催乳素水平以及脂质和碳水化合物特征标志物方面，PCOS 病例和/或对照组之间 TP53 基因型的频率没有统计学差异（P>0.05）。分子动力学预测显示，17p13.1 位置（rs1042522）的错义取代可能改变 p53 蛋白的性质和二级结构。作为遗传风险因素，TP53 变异可能在伊朗女性 PCOS 的发病机制中发挥关键作用。需要对其他种族进行基于人群的复制研究，以发现 TP53 变体或位于其他 TSG 中的 SNP 对这种内分泌疾病病因的遗传贡献。
