Haplotype Analysis of Candidate Genes Involved in Inflammation and Oxidative Stress and the Susceptibility to Preeclampsia

Abstract

Unbalanced inflammatory reactions and oxidative stress are inseparably interconnected, and both may play crucial roles in the pathophysiological mechanisms of preeclampsia (PE). In the published previous studies, we have genotyped for SNPs that related to inflammation (rs2227485, rs153109, rs17855750, rs2027432, rs2275913, rs763780, rs4819554, and rs13015714) and oxidative stress (rs1695, rs4680, rs1800566, rs4807542, rs713041, rs7579, rs230813, rs1004467, rs3824755, and rs9932581) to investigate whether these polymorphisms were associated with susceptibility to PE in a Chinese Han population. In this present study, we collected these data of experimental and clinical from above studies for haplotype analysis of inflammation-related SNPs in 631 PE patients and 720 normal pregnancy and oxidative stress-related SNPs in 342 PE patients and 457 normal pregnancies for susceptibility to PE. The data of genotype distribution and allele frequency comparisons after correction for multiple comparisons (P/8 or P/10) showed 2 among the 8 candidate inflammation-related SNPs have significant differences (rs2027432 genotype χ2=407.377,p<0.001,p<0.00625). Moreover, the minor alleles of rs2027432 T (minor allele χ2=450.923,p<0.001,p<0.00625;OR=21.439,95%CI=15.181‐30.278) and rs4819554 G (minor allele χ2=163.465,p<0.001,p<0.00625;OR=5.814,95%CI=4.380‐7.719) were confirmed as risk allele of PE, respectively. Our analysis revealed rs2027432 (TT) of NLRP3 and rs4819554 (GG) of IL-17RA are risk factors for PE. However, no significant difference was found at the oxidative stress-related SNPs. In the candidate loci for oxidative stress, we also identified 3 SNP matches (rs4807542 and rs713041, rs230813 and rs75799, rs1004467 and rs3824755) that had high linkage disequilibrium (LD) with each other and were selected as a block (r2=0.98,r2=0.97,r2=0.97,r2>0.9), and the GT and GC haplotypes of rs4807542 and rs713041 in GPX4 showed significant differences between the PE and control groups (χ2=5.143,p=0.0233,p<0.05;χ2=6.373,p=0.0116,p<0.05). So, we inferred that polymorphisms of NLRP3 rs2027432 and IL-17RA rs4819554, which are related to inflammation, and the rs713041 variant of GPX4, which is related to oxidative stress, were associated with susceptibility to PE. The GT and GC haplotypes of rs4807542 and rs713041 in GPX4 may increase the risk of PE in the Chinese Han population.

Multiple genetic variations of chronic rhinosinusitis with nasal polyps are associated with respiratory parameters in men with obstructive sleep apnea

“…It has been reported that the interleukin-33 SNP rs1888909 is associated with an increased risk of hay fever in high linkage disequilibrium via interaction with rs928413 and rs1342326 [32]. The GPX4 SNP rs4807542 was reported to be associated with Kashin-Beck disease, biliary tract cancer, and preeclampsia in a Chinese Han population [33][34][35]. To date, few studies have investigated SNPs rs1444782, rs338598, rs6543124, rs8046011, rs28383314, and rs62408225.…”

Association of a non-synonymous SNP of IL17RA gene with litter size traits in Large White and Landrace pigs

“…Although the association of IL17A polymorphism with reproduction traits has been scarcely studied, a previous study has demonstrated that the human IL17RA (rs4819554) polymorphism is associated with the pregnancy disorder of preeclampsia in a Chinese Han population (Chen et al, 2020). Conversely, there is no association of the human IL17RA polymorphism with preeclampsia in Chinese women (Wang et al, 2015).…”

“…Moreover, IL17 and IL17R are implicated in various reproductive processes including implantation, placentation, and maintenance of pregnancy (Pongcharoen et al, 2006;Pongcharoen and Supalap, 2009;Saito et al, 2011). Genetic polymorphisms and abnormal expression of IL17 and/or IL17R are associated with the pregnancy disorders of preeclampsia, recurrent implantation failure, and recurrent pregnancy loss in women (Najafi et al, 2014;Zidan et al, 2015;Wang et al, 2019;Chen et al, 2020).…”

“…The porcine IL17RA polymorphisms have been characterized with 630 variant alleles (consisting of 122 upstream, 8 non-synonymous, 15 synonymous, 356 intronic, and 129 downstream variants) and exhibited in the Ensembl database (ENSSSCT00000033369.3, https://www.ensembl.org/Sus_scrofa/Info/Index, online access 23.10.2020). The association of the polymorphisms of the IL17RA gene with the pregnancy disorder of preeclampsia has been investigated in humans (Wang et al, 2015;Chen et al, 2020). The downregulated IL17RA expressed is related to preeclampsia (Ma et al, 2019).…”

The genetic risk factors for pregnancy‐induced hypertension: Evidence from genetic polymorphisms

“…Oxidative stress is defined as an imbalance between oxidants and antioxidants in the body, 9 that induces endothelial dysfunction, poor placental perfusion, and systemic inflammatory responses 66 . Evidence has also supported the involvement of oxidative stress in the activation nuclear factor kappa‐B (NF‐κB) pathway, which can promote the release of inflammatory factors and adhesion molecules ultimately affecting involved in the occurrence of PIH 9 …”