Association between polymorphisms rs2228001 and rs2228000 in XPC and genetic susceptibility to preeclampsia: a case control study

Preeclampsia (PE) is defined as a special disease that occurs after 20 weeks of pregnancy, with hypertension and proteinuria or one of the following characteristics, thrombocytopenia, liver and kidney function damage, and pulmonary oedema [1], and seriously affects maternal and child health and even leads to death or morbidity during the perinatal period [2]. Although the potential harm of PE has been extensively studied, its pathogenesis remains poorly understood, and many factors may be involved in the development of PE, including inflammatory reactions, placental ischemia, vascular endothelial dysfunction, genetic factors, and oxidative stress [3‐5].

Compared with normotensive pregnant women, patients with PE are in a state of extremely increased oxidative stress because of the decreased antioxidant capacity. Excess production of reactive oxygen species (ROS) can lead to vascular endothelial and DNA damage, which may be involved in the pathogenesis of PE by blocking trophoblast invasion and placental formation [6, 7]. A comet assay revealed significantly increased levels of DNA damage in the placenta of PE model rats [8]. As a sensitive indicator of DNA damage, phosphorylated H2AX was highly expressed not only in PE placentas but also in maternal metaphase stromal cells cultured in vitro with oxides [9]. Consistent with this result, Takagi et al. [10] found that 8-hydroxy-20-deoxy-guanosin (8-OHdG), a representative DNA damage marker, was detected at higher concentrations in the serum of patients with PE than in healthy pregnant women. There are enzymes related to DNA repair in the human body that can repair these damaged DNA and maintain a stable state of genetic material [11]. Therefore, it is essential to explore the role of genetic polymorphisms in the DNA repair system in PE pathogenesis based on DNA damage.

As a damage recognition protein of DNA, the gene Xeroderma pigmentosum complementation group C (XPC), which belongs to one of the key genes in the nucleotide excision repair system [12], repairs the damaged DNA by nucleotide excision to reduce the damage to DNA, and then reduces the attack of oxidative stress on organisms [13]. The XPC proteins have specific roles in cell protection and repair and tolerance of ROS-induced DNA damage [14]. In addition, reducing or silencing the expression of XPC increases the level of intracellular ROS, which increases oxidative stress and ultimately leads to oxidative DNA damage [15]. Two nonsynonymous single nucleotide polymorphisms (SNPs), c.2815G > T (p.Q939E, rs2228001) in exon 16 and c.1496C > T (p.A499V, rs2228000) in exon 9 of XPC may alter the capacity of XPC and modulate risk of various cancers [16, 17]. The positions of the two SNPs on the chromosomes are shown in Fig. 1. Currently, there is a lack of research on the association between these two SNPs and PE susceptibility. Therefore, the present study aimed to investigate the relationship between polymorphisms of rs2228001 and rs2228000 in XPC and the susceptibility to PE in the Chinese Han population, which further provides an experimental basis for a follow-up clinical study on PE.

There are many studies on the role of genetic polymorphisms in susceptibility to female diseases such as uterine fibroids, recurrent spontaneous abortion, and polycystic ovary syndrome (PCOS). The levels of anti-Müllerian hormone (AMH) were found to be significantly higher in patients with PCOS than in healthy women; however, findings regarding the association between AMH polymorphisms and the development of PCOS were inconsistent. Therefore, Wang et al. conducted a meta-analysis of five studies and found that AMH genetic variants may not be related to PCOS risk [18]. A genome-wide association study in a Japanese population revealed that nine SNP loci were considered risk factors for uterine leiomyoma, further indicating the important role of genetic factors in uterine leiomyoma [19]. Salimi et al. [20] suggested that SNPs of the HOX transcript antisense RNA gene, such as rs12826786, rs920778, and rs1899663, are related to the development of RSA. Previous studies have reported that women whose mothers and sisters have a history of PE have an elevated risk of PE, which provides evidence for the important role of genetic factors in PE. A common complication of pregnancy, PE is responsible for 7 to 10% of maternal morbidity worldwide [21‐23], and is caused by many factors, including endothelial damage, inflammatory response, oxidative stress, and placental factors; among which the role of oxidative stress should not be ignored [5, 24]. Patients with PE are in a state of increased oxidative stress, and excessive amounts of oxidants can result in damage to lipids, proteins, and DNA. Damaged DNA can be repaired by DNA repair mechanisms, which are essential for the stability of the genetic material.

However, only a few studies have reported an association between DNA repair system polymorphisms and PE risk. A previous study has shown that in the Iranian population, Arg399Gln of X-ray repair cross-complementing group 1 (XRCC1) is associated with PE susceptibility, and the allele 399Gln is considered a risk factor for PE [25]. This result contradicted another study in the Mexican population in which xeroderma pigmentosum group D (XPD) Lys751Gln, XRCC Arg399Gln, and XRCC3 Thr241Met polymorphisms were not associated with the risk of PE [26]. This discrepancy in results may be due to racial differences. Moslehi et al. found positive links between specific XPD variants in the foetal genome and the risk of placental maldevelopment and PE [27]. Among the Turkish population, Vural et al. studied three SNP sites on DNA repair genes in XRCC1, Apurinic endonuclease 1, and XPD, indicating that these three SNPs may not be related to the onset of PE [28]. Although the study included important genes in the DNA repair system, its small sample size limited its representativeness. In our previous study, we investigated the association between polymorphisms of the other three core genes in the nucleotide excision repair pathway and PE risk and found that XPA rs1800975, XPF rs1799801, and XPG rs17655 were not significantly correlated with the risk of PE as a whole in Chinese Han women [29].

As an initiator of the nucleotide excision repair process, XPC, located in the short arm of chromosome 3 (3p25), plays a key role in DNA damage recognition by binding to the radiation repair 23 B (RAD23B) protein to form the XPC-RAD23B complex. Relevant studies have found that the expression of XPC can downregulate the expression of ROS and lead to a change in metabolism [15]. In addition, many studies have indicated that XPC polymorphisms are associated with the risk of oesophageal squamous cell carcinoma and gastric cardiac adenocarcinoma [30]. Therefore, we hypothesised that the genetic polymorphism of XPC is related to the occurrence of PE to explore the possible pathogenesis of PE.

In our study, 1276 normal pregnant women and 958 patients with PE were enrolled. Genotyping of the two loci rs2228000 and rs2228001 in XPC, found that there were significant differences in genotypic and allelic frequencies of rs2228000 between the PE and control groups, and allele T may act as a protect factor. However, no difference was observed in rs2228001 between two groups. To further explore the relationship between them, PE was divided into mild and severe and early-onset and late-onset PE categories. The results generally consistent with those of the large sample data. Then, haplotype analysis showed that AC and AT may be associated with the pathogenesis of PE. Therefore, this study suggests that rs228000 in XPC may be associated with the risk of PE in Chinese Han women and allele T was considered as a protective factor in the pathogenesis of PE.