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Potential role for nectin-4 in the pathogenesis of pre-eclampsia: a molecular genetic study.

ABSTRACT: BACKGROUND:Nectins are cell adhesion molecules that play a pivotal role in adherens junctions and tight junctions. Our previous study using whole-genome oligonucleotide microarrays revealed that nectin-4 was upregulated in pre-eclamptic placentas. We investigated the role of nectin-4 in the etiology of pre-eclampsia. METHODS:We investigated the expression of nectin-4 using real-time RT-PCR, western blot and immunostaining. Additionally, we performed matrigel invasion assay and cytotoxicity assay using cells overexpressing the nectin-4. RESULTS:NECTIN4 transcripts were elevated in pre-eclamptic placentas relative to uncomplicated pregnancies. Nectin-4 protein levels in pre-eclamptic placentas were higher on a semi-quantitative western blot. Nectin-4 was localized at the apical cell membrane in syncytiotrophoblast cells and not at the adherens junctions. Nectin-4 was also detected in cytotrophoblasts and a subset of cells in the decidua. Nectin-4 overexpressing trophoblast cells migrated normally in the matrix. However, Natural killer (NK) cells showed a strong cytotoxic effect against nectin-4 overexpressing trophoblast cells. No causative genetic variation was evident in the NECTIN4 gene from a pre-eclamptic placenta. CONCLUSIONS:There are as yet unknown factors that induce nectin-4 overexpression in trophoblast cells that may contribute to abnormal placentation via an aberrant immune response and the onset of a pre-eclamptic pregnancy.

SUBMITTER: Ito M

PROVIDER: S-EPMC6137934 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Potential role for nectin-4 in the pathogenesis of pre-eclampsia: a molecular genetic study.

Ito Mayuko M Nishizawa Haruki H Tsutsumi Makiko M Kato Asuka A Sakabe Yoshiko Y Noda Yoshiteru Y Ohwaki Akiko A Miyazaki Jun J Kato Takema T Shiogama Kazuya K Sekiya Takao T Kurahashi Hiroki H Fujii Takuma T

BMC medical genetics 20180914 1

<h4>Background</h4>Nectins are cell adhesion molecules that play a pivotal role in adherens junctions and tight junctions. Our previous study using whole-genome oligonucleotide microarrays revealed that nectin-4 was upregulated in pre-eclamptic placentas. We investigated the role of nectin-4 in the etiology of pre-eclampsia.<h4>Methods</h4>We investigated the expression of nectin-4 using real-time RT-PCR, western blot and immunostaining. Additionally, we performed matrigel invasion assay and cyt ...[more]

PMID: 30217189

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Project description:BackgroundPre-eclampsia is the most common complication occurring during pregnancy. In the majority of cases, it is concurrent with other pathologies in a comorbid manner (frequent co-occurrences in patients), such as diabetes mellitus, gestational diabetes and obesity. Providing bronchial asthma, pulmonary tuberculosis, certain neurodegenerative diseases and cancers as examples, we have shown previously that pairs of inversely comorbid pathologies (rare co-occurrences in patients) are more closely related to each other at the molecular genetic level compared with randomly generated pairs of diseases. Data in the literature concerning the causes of pre-eclampsia are abundant. However, the key mechanisms triggering this disease that are initiated by other pathological processes are thus far unknown. The aim of this work was to analyse the characteristic features of genetic networks that describe interactions between comorbid diseases, using pre-eclampsia as a case in point.ResultsThe use of ANDSystem, Pathway Studio and STRING computer tools based on text-mining and database-mining approaches allowed us to reconstruct associative networks, representing molecular genetic interactions between genes, associated concurrently with comorbid disease pairs, including pre-eclampsia, diabetes mellitus, gestational diabetes and obesity. It was found that these associative networks statistically differed in the number of genes and interactions between them from those built for randomly chosen pairs of diseases. The associative network connecting all four diseases was composed of 16 genes (PLAT, ADIPOQ, ADRB3, LEPR, HP, TGFB1, TNFA, INS, CRP, CSRP1, IGFBP1, MBL2, ACE, ESR1, SHBG, ADA). Such an analysis allowed us to reveal differential gene risk factors for these diseases, and to propose certain, most probable, theoretical mechanisms of pre-eclampsia development in pregnant women. The mechanisms may include the following pathways: [TGFB1 or TNFA]-[IL1B]-[pre-eclampsia]; [TNFA or INS]-[NOS3]-[pre-eclampsia]; [INS]-[HSPA4 or CLU]-[pre-eclampsia]; [ACE]-[MTHFR]-[pre-eclampsia].ConclusionsFor pre-eclampsia, diabetes mellitus, gestational diabetes and obesity, we showed that the size and connectivity of the associative molecular genetic networks, which describe interactions between comorbid diseases, statistically exceeded the size and connectivity of those built for randomly chosen pairs of diseases. Recently, we have shown a similar result for inversely comorbid diseases. This suggests that comorbid and inversely comorbid diseases have common features concerning structural organization of associative molecular genetic networks.

Project description:ObjectiveThe aim of this study was to investigate the relationship between potential functional single-nucleotide polymorphisms (SNPs) of the angiotensin-converting enzyme 2 (ACE2) gene and the pathogenesis of pre-eclampsia (PE) in Guangxi, China.Materials and methodsA case-control study was conducted involving 327 PE cases and 591 age-matched, normal, singleton pregnant women. Potential functional ACE2 gene variants (rs2106809 A>G, rs6632677 G>C, and rs2074192 C>T) were selected and genotyped using kompetitive allele-specific PCR. The strength of the associations between the studied genetic variants and the risk of PE were evaluated using odds ratios (ORs) and corresponding 95% confidence intervals (CIs).ResultAfter adjusting for age and body mass index (BMI), unconditional logistic regression analysis showed that rs2106809 A>G was significantly associated with PE risk (AG vs. AA, OR = 1.43, 95% CI = 1.03-1.99, p = 0.034; AG/GG vs. AA, OR = 1.45, 95% CI = 1.06-1.99, p = 0.019), especially with severe PE (AG vs. AA, adjusted OR = 1.70, 95% CI = 1.10-2.61; AG/GG vs. AA, adjusted OR = 1.71, 95% CI = 1.14-2.57). Further stratified analysis showed that rs2106809 was even more pronounced in subjects in the pre-pregnancy BMI (pre-BMI) >23 kg/m2 (adjusted OR = 2.14, 95% CI = 1.32-3.45) and triglyceride (TG) >2.84 mmol/L subgroups (adjusted OR = 1.81, 95% CI = 1.09-3.01) under the dominant genetic model. We also found that rs2106809 interacted with pre-BMI (p interaction = 0.040), thereby affecting an individual's genetic susceptibility to PE. Multiple dimension reduction analysis demonstrated that rs2106809 made the best one-locus model, and the three-locus model was the best interaction model for predicting PE risk. Functional analysis suggested that rs2106809 A>G causes a change in the reliability of classifications of two putative splice sites in the ACE2 gene, potentially regulating the expression of functional genes (PIR, ACE2, and CLTRN) in multiple tissues and cell lines (p< 0.05).ConclusionThe ACE2 gene rs2106809 A>G variant is significantly associated with the risk of PE via individual locus effects and/or complex gene-gene and gene-environment interactions. Regulating the expression of functional genes such as PIR, ACE2, and CLTRN may be the molecular mechanism by which rs2106809 increases an individual's susceptibility to PE.

Dataset Information

Potential role for nectin-4 in the pathogenesis of pre-eclampsia: a molecular genetic study.

Publications

Potential role for nectin-4 in the pathogenesis of pre-eclampsia: a molecular genetic study.

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