The typical manifestation of PIH is BP elevation. Women with a history of PIH are more susceptible to chronic hypertension，and women with chronic hypertension are at increased risk for PE. Luscher demonstrated that endothelial cell injury in PIH women could profoundly affect cardiovascular function, and patients were likely to become hypertensive, hyperlipidemic, and eventually develop atherosclerosis with aging. Ellen et al. reported that women with chronic hypertension had an increased rate of PE (17-25%, vs. 3-5% in the general population). Women with chronic arterial hypertension were also at increased risk for superimposed PE . Except for similar metabolic bases, PIH and hypertension share some genetic risk factors. Our team had found significant associations between angiotensinogen (AGT) rs3789678 and GH and between angiotensin II receptor type 1 (AGTR1) rs275645 and PE after adjusting for fetal sex, maternal age, and gestational diabetes mellitus (GDM) . So validate the association between hypertension candidate genes and PIH is a reasonable and effective way to find genetic risk factors for PIH.
In this case-control study, significant differences were found between MED13L rs11067763 and GH/PE, and SLC4A7 rs820430 associated with the onset and development of GH/PE. In detail, carrying the GG genotype at rs11067763 was a protective factor for developing GH/PE. As for rs820430, carrying the AA genotype was a risk factor for developing GH/PE. But no significant association between CYP21A2 rs2021783 polymorphisms and GH/PE was found. Importantly, our study reveals for the first time that the MED13L rs11067763 and SLC4A7 rs820430 were associated with GH/PE risk among Chinese Han women.
MED13L is a paralog of the closely related protein named Mediator complex subunit 13 (MED13), which is believed to have arisen from gene duplication events. It is responsible for bridging the RNA pol II enzyme and transcription factors to initiate transcription of protein-coding genes and non-coding RNA genes . Through retinoblastoma (Rb)/E2F pathways, it promotes proliferation of vascular smooth muscle cells which are important in the development of hypertension . Besides, several researches have shown an indirect association between MED13L and inflammation through Wnt pathway which plays a regulatory role in immune system. Moreover, MED13L regulates the expression level of activating transcription factor 4 (ATF4) which regulates the secretion of pro-inflammatory cytokines such as interleukin (IL)-6 and IL-8[26, 27], and these two cytokines have been considered influencing the onset of GH and PE. As Adela et al. reported, the serum level of IL-6 decreased in GH subjects . Besides, Krasnyi found that increased endothelial IL-8 expression represented endothelial dysfunctions, which are significant pathophysiologic features of PE . In our study, we found genetic variants of MED13L rs11067763 associated with development of GH/PE in Chinese Han women. GG genotype at rs11067763 has shown to be a protective factor for GH/PE. Thus, more studies are needed to validate the association in larger population, and researches on mechanisms are necessary to uncover the molecular pathways of the association.
SLC4A7 gene is on chromosome 3p24.1, it belongs to the SLC4 family . SLC4A7 encodes the electroneutral Na+/HCO-3, co-transporter NBCn1. Several researchers have demonstrated that NBCn1 has a role in controlling intracellular pH (pHi) in vascular smooth muscle cells (VSMCs), and pHi is a determinant of VSMCs contractility and endothelial function, both of which effect BP. Furthermore, through elevated steady-state pHi and accelerated recovery from intracellular acidosis, they also found genetic variants of SLC4A7 rs13082711 associated with increased SLC4A7 expression level and NBCn1 function.[31-34]. A large scale GWAS also detected association between polymorphisms of SLC4A7 rs13082711 and SBP/DBP . A study included 275 participants from rural district of Shandong Province of China indicated rs820430 functioned as an enhancer of SLC4A7 . Besides, NBCn1 promotes arterial remodeling which can cause luminal narrowing and obstruct blood flow . It is known to us that increased vascular resistance, invasion of placental trophoblast, and failed remodeling of uterine spiral arterial are pathological bases of PIH. Therefore variants of SLC4A7 might associate with the onset of PIH through several pathways such as BP regulation, and remodeling of arterial. We reported the polymorphisms of SLC4A7 rs820430 was associated with the onset of GH and PE in Chinese Han women for the first time. AA genotype at rs820430 is a risk genotype for GH and PE, and A allele at rs820430 is a risk allele for GH. However, more studies are needed to identify pathophysiological path from PIH associated genetic variation, to gene expression, and subsequently to gene function of SLC4A7 that alters cellular behavior.
CYP21A2 is located on chromosome 6 within the HLA (human leukocyte antigen) locus. It encodes 21-hydroxylase enzyme, a member of the cytochrome P450 (CYP450) superfamily . 21-hydroxylase enzyme is necessary to the synthesis of cortisol and aldosterone, the latter regulates the amount of salt retained by the kidneys and then affects blood volume of body and BP. The mutation of CYP21A2 is related to congenital adrenal hyperplasia (CAH) . Many studies have investigated the consequences of the mutations of the CYP450 superfamily. Though Chatuphonprasert et al. found the association between PE and altered expression of CYP27A1 protein in placenta, maternal, and/or fetal serum , another research conducted in a Korean population detected no significant association between polymorphisms in CYP1A1gene and PE . Also, a Spanish study included 500 Caucasians from the region of Asturias indicated that the variation in CYP3A5, CYP3A4, and CYP21A2 did not contribute to the risk for PIH . Similarly, in our study no significant association has been observed between variants of CYP21A2 rs2021783 and PIH.
Our case-control study was limited by the small sample size. It is difficult to identify very weak associations between SNP and PIH. This issue is common in gene-association studies. Although we did not detect significant difference between fetal sex and PIH, the proportions of female fetus in GH and PE groups were higher than those in control group. Different from the systematic review, we found primipara were less likely to develop PE. It was due to the unequal proportion of primipara and multipara in our study. In order to detect accurate relations, we still set fetal sex and primipara as covariates in multiple logistic regression. Another limitation of our study is that the gestational age of PE onset and medical regimens were not regularly recorded in the medical records of our study region, we did not conduct subgroup analyses according to early- or late-onset PE and did not categorize PE cases by severity. Also, we did not adjust for family history of hypertension or PIH and pre-pregnancy body mass index (BMI) in the multiple logistic regression because the proportion of missing data for it was larger than 15%. Further researches with larger sample size and more comprehensive clinical characteristics are necessary to investigate the disease-related genes in GH and different types of PE.