Pregnancy-associated Plasma protein-A Gene Research Articles

Pregnancy-associated plasma protein-A gene polymorphisms in patients with periodontitis

Pregnancy-associated plasma protein-A gene polymorphisms in patients with periodontitis

Abstract 108: Insulin-like growth factor binding protein 4 exerts differential effects on breast cancer cell proliferation based on the expression status of pregnancy-associated plasma protein A

Abstract Insulin-Like Growth Factor Binding Protein 4 (IGFBP-4) is one of six binding proteins involved in sequestering insulin-like growth factors 1 and 2 (IGFs). IGFBP-4 expression is induced by estrogen receptor α (ERα), and its classical function is to prevent activation of IGF-1 receptor (IGF-1R) by sequestration of IGF-1. However, the aggressive triple-negative breast cancer cell line MDA-MB-231 shows high expression of IGFBP-4 along with its protease, pregnancy-associated plasma protein A (PAPP-A). Further, inhibition of IGFBP-4 in MDA-MB-231 cells is sufficient to reduce migration. To better understand the function of IGFBP-4 as a pro-cancer or anti-cancer protein, its anti-proliferative effects in ERα positive cells must be reconciled with its pro-migratory effects in triple negative cells. The role of IGFBP-4 in proliferation across four breast cancer cell lines representing ERα positive and triple negative subtypes was investigated. Stable transfection with IGFBP-4 expression construct in the MCF-7 and T-47D cell lines, which have silenced the PAPP-A gene, shows a reduction in proliferation. Further, MCF-7 parental cells cultured in conditioned media containing IGFBP-4 also show reduced proliferation, suggesting that the anti-proliferative effect of IGFBP-4 is associated with the absence of PAPP-A. Stable IGFBP-4 transfection of triple-negative MDA-MB-468 cell line, which has low extracellular IGFBP-4 when compared to MDA-MB-231 but does express PAPP-A, was sufficient to increase proliferation. Taken together, these results support the conclusion that proliferative effects of IGFBP-4 are dependent upon the expression status of PAPP-A. Citation Format: Keenan L. Flynn, Kevin D. Houston. Insulin-like growth factor binding protein 4 exerts differential effects on breast cancer cell proliferation based on the expression status of pregnancy-associated plasma protein A [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 108.

Genetic and Pharmacological Inhibition of PAPP-A Protects Against Visceral Obesity in Mice.

Pathogenicity of visceral adipose tissue (VAT) has been linked to the metabolic stress of enlarging mature adipocytes and a limited ability to recruit new adipocytes. One of the major distinguishing features of VAT preadipocytes is the high expression of the zinc metalloprotease, pregnancy-associated plasma protein-A (PAPP-A), when compared to subcutaneous adipose tissue (SAT). In this study we used 2 different approaches to investigate the effect of PAPP-A inhibition on different fat depots in mice on a high-fat diet (HFD) for 15 weeks. Conditional knockdown of PAPP-A gene expression in female adult mice resulted in significant decreases of 30% to 40% in adipocyte size in VAT (mesenteric and pericardial depots) compared to control mice. There was no effect on SAT (inguinal) or intra-abdominal perigonadal fat. Liver lipid was also significantly decreased without any effect on heart and skeletal muscle lipid. We found similar effects when using a pharmacological approach. Weekly injections of a specific immunoneutralizing monoclonal antibody (mAb-PA 1/41) or isotype control were given to male and female wild-type mice on HFD for 15 weeks. Adipocyte size was significantly decreased (30%-50%) only in VAT with mAb-PA 1/41 treatment. In this model, cell number was significantly increased in mesenteric fat in mice treated with mAb-PA 1/41, suggesting hyperplasia along with reduced hypertrophy in this VAT depot. Gene expression data indicated a significant decrease in F4/80 (macrophage marker) and interleukin-6 (proinflammatory cytokine) and a significant increase in adiponectin (anti-inflammatory adipokine with beneficial metabolic effects) in mesenteric fat compared to inguinal fat in mice treated with mAb-PA 1/41. Furthermore, there was significantly decreased liver lipid content with mAb-PA 1/41 treatment. Thus, using 2 different models systems we provide proof of principle that PAPP-A inhibition is a potential therapeutic target to prevent visceral obesity and its metabolic sequelae, such as fatty liver.

Association of Polymorphism in Gene of Pregnancy-Associated Plasma Protein A (PAPPA) and Preeclampsia

Background: Preeclampsia is a common disorder of pregnancy. Current study was conducted to determine the association of polymorphism in gene of pregnancy-associated plasma protein A (PAPPA) and preeclampsia.Methods: In this prospective cohort study, 134 pregnant women were consecutively enrolled and the blood sampling was performed for genetic analysis in a single lab. Then the subjects were followed-up for preeclampsia and it was seen that 34 women developed preeclampsia and the polymorphism of PAPPA gene was compared between those with and without preeclampsia.Results: The results demonstrated that despite twice higher proportion of CC condition of PAPPA in those with preeclampsia in comparison with those with normal pregnancy, there was no significant difference between two groups (P > 0.05).Conclusions: Totally, according to the obtained results, it may be concluded that polymorphism of pregnancy-associated plasma protein A is not related to occurrence of preeclampsia in pregnant women.

Genomic association for sexual precocity in beef heifers using pre-selection of genes and haplotype reconstruction.

Reproductive traits are of the utmost importance for any livestock farming, but are difficult to measure and to interpret since they are influenced by various factors. The objective of this study was to detect associations between known polymorphisms in candidate genes related to sexual precocity in Nellore heifers, which could be used in breeding programs. Records of 1,689 precocious and non-precocious heifers from farms participating in the Conexão Delta G breeding program were analyzed. A subset of single nucleotide polymorphisms (SNP) located in the region of the candidate genes at a distance of up to 5 kb from the boundaries of each gene, were selected from the panel of 777,000 SNPs of the High-Density Bovine SNP BeadChip. Linear mixed models were used for statistical analysis of early heifer pregnancy, relating the trait with isolated SNPs or with haplotype groups. The model included the contemporary group (year and month of birth) as fixed effect and parent of the animal (sire effect) as random effect. The fastPHASE® and GenomeStudio® were used for reconstruction of the haplotypes and for analysis of linkage disequilibrium based on r2 statistics. A total of 125 candidate genes and 2,024 SNPs forming haplotypes were analyzed. Statistical analysis after Bonferroni correction showed that nine haplotypes exerted a significant effect (p<0.05) on sexual precocity. Four of these haplotypes were located in the Pregnancy-associated plasma protein-A2 gene (PAPP-A2), two in the Estrogen-related receptor gamma gene (ESRRG), and one each in the Pregnancy-associated plasma protein-A gene (PAPP-A), Kell blood group complex subunit-related family (XKR4) and mannose-binding lectin genes (MBL-1) genes. Although the present results indicate that the PAPP-A2, PAPP-A, XKR4, MBL-1 and ESRRG genes influence sexual precocity in Nellore heifers, further studies are needed to evaluate their possible use in breeding programs.

Pregnancy-associated plasma protein A gene polymorphism in pregnant women with preeclampsia and intrauterine growth restriction

Preeclampsia (PE) and intrauterine growth restriction (IUGR) are still among the most commonly researched titles in perinatology. To shed light on their etiology, new prevention and treatment strategies are the major targets of studies. In this study, we aimed to investigate the relation between gene polymorphism of one of the products of trophoblasts, pregnancy-associated plasma protein A (PAPP-A) and PE/IUGR.A total of 147 women (IUGR, n = 61; PE, n = 47; IUGR + PE, n = 37; eclampsia, n = 2) were compared with 103 controls with respect to the sequencing of exon 14 of the PAPP-A gene to detect (rs7020782) polymorphism. Genotypes “AA” and “CC” were given in the event of A or C allele homozygosity and “AC” in A and C allele heterozygosity. Our findings revealed that the rate of AA, CC homozygotes, and AC heterozygotes did not differ between groups. Moreover, there was no difference in the distribution of PAPP-A genotypes among the patients with IUGR, PE, IUGR + PE, or eclampsia. Finally, birth weight, rate of the presence of proteinuria, and total protein excretion on 24-hour urine were similar in the subgroups of AA, AC, and CC genotypes in the study group. Our study demonstrated no association between PAPP-A gene rs7020782 polymorphism and PE/IUGR.

Correlation of single nucleotide polymorphisms in the pregnancy-associated plasma protein-A gene with carotid plaques.

BackgroundPregnancy-associated plasma protein A (PAPP-A) is abundantly expressed in carotid plaques. This study investigated the association between single nucleotide polymorphisms (SNPs) of PAPP-A and the presence of carotid plaques.MethodsA total of 408 patients with carotid plaques and 493 controls were included in the study. All subjects were Southern Chinese Han. Carotid plaques were analyzed by computer tomography angiography. PAPP-A SNPs were identified by ligase detection reaction-polymerase chain reaction analysis. The PAPP-A genotypes rs3747823, rs7020782, and rs13290387 were analyzed.ResultsThe rs7020782 C allele genotype correlated with an increased risk of developing carotid plaques under the dominant, recessive, and additive models (adjusted odds ratios: 2.60, 2.36, and 3.48, respectively; P ≤ 0.001). Only C allele-carrying genotypes correlated with a significantly increased risk of carotid plaque based on studies stratified by age and sex under the dominant model. rs7020782 remained significantly associated with the risk of carotid plaque calcification after adjusting for age and potential confounders (adjusted odds ratio, 1.89; 95 % confidence interval, 1.17–3.08; P = 0.010).ConclusionsThis study found, for the first time, that the A˃C variation of rs7020782 might be an independent risk factor for carotid plaque development and calcification. The determination of such genotypes could provide a new tool for identifying individuals at high risk for carotid atherosclerosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12872-015-0041-1) contains supplementary material, which is available to authorized users.

Abstract P4-02-11: Circulating methylated DNA of pregnancy-associated plasma protein A as a clinically useful biomarker in breast cancer

Abstract Background: A recent report suggests that Pregnancy-Associated Plasma Protein A (PAPPA) plays a pivotal role in normal cell division and is targeted early in breast cancer development. Epigenetic silencing of PAPPA is highly prevalent in precursor lesions and invasive breast cancer, correlating with loss of PAPPA protein expression. In normal breast tissue PAPPA promoter methylation was not observed (Journal of Pathology 344-356: 2014). We sought to test the hypothesis that PAPPA promoter hypermethylation can be detected in cell-free tumour specific DNA (ctDNA) in the bloodstream of patients with metastatic breast cancer. Methods: Plasma derived from 12 patients with metastatic breast cancer was examined for ctDNA. A semi-quantitative real-time PCR based MethyLight assay was used for detection of PAPPA methylation. Spiking experiments with breast cancer cell lines were performed to develop the assay and confirm linearity of sodium bisulfite treatment. Results: Percentage methylated reference (PMR) values from spiking experiments with PAPPA methylated and non-methylated DNA in plasma (matrix) demonstrate good linearity for the PAPPA gene and the endogenous control Col2A. PAPPA methylation was detected in 10 out of 12 (83%) of the metastatic breast cancer samples. In stark contrast, epigenetic silencing of PAPPA was not detected in any of the plasma samples from non-cancer bearing patients (n=10). Conclusions: Given the potential clinical impact of our data, this study is being extended to include early stage breast cancer patients with poor prognostic clinic-pathological indicators. Our proof-of-concept findings indicate that testing for PAPPA promoter methylation in ctDNA may be used as a biomarker of disseminated disease, helping clinicians with treatment decisions and adjusting those choices as conditions change. By developing and refining more sensitive techniques, PAPPA methylation testing in ctDNA could also find practical utility in breast cancer screening. Citation Format: Richard Sainsbury, Karsten Koehler, Catherine Page, Saroj Velamakanni. Circulating methylated DNA of pregnancy-associated plasma protein A as a clinically useful biomarker in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-02-11.

Inducible Reduction in Pregnancy-Associated Plasma Protein-A Gene Expression Inhibits Established Atherosclerotic Plaque Progression in Mice

Pregnancy-associated plasma protein-A (PAPP-A) is a novel zinc metalloproteinase implicated in cardiovascular disease. The aim of this study was to determine whether a reduction in PAPP-A expression in the adult affects the progression of established atherosclerotic plaque. Apolipoprotein E-null mice were fed a high-fat diet for 5 weeks to initiate early-stage plaque development before tamoxifen-inducible, Cre recombinase-mediated excision of the floxed PAPP-A gene. High-fat feeding was continued, and after 10 weeks the aorta and brachiocephalic artery were harvested for atherosclerotic plaque analyses of overall burden and morphology, respectively. An inducible decrease in PAPP-A gene expression significantly inhibited atherosclerotic plaque progression as assessed by a 70% reduction in plaque burden in the aorta (P = .012) without an effect on the elevated circulating levels of cholesterol and triglycerides in this model. Furthermore, this reduction in PAPP-A prevented the development of advanced plaque with necrotic cores and buried fibrous caps in the brachiocephalic artery. These data indicate PAPP-A as a potential target to limit progression of established atherosclerotic plaque.

Association of pregnancy-associated plasma protein-A gene polymorphism with ischemic stroke in northern Chinese Han population

Objectives: The pregnancy-associated plasma protein-A (PAPP-A), belonging to the metalloproteinase superfamily, plays an important role in destabilization of atherosclerotic plaques. The aim of this study is to evaluate whether PAPP-A gene polymorphism is associated with the risk of ischemic stroke (IS) in northern Chinese Han populations.Methods: A total of 368 patients with IS and 374 aged-matched healthy controls in a Chinese Han population were included in the case–control study. The single-nucleotide polymorphism (SNP) IVS6+95 (rs13290387) in the PAPP-A gene was analyzed by the polymerase chain reaction–ligation detection reaction (PCR–LDR) method.Results: Compared with the GG+CG genotype, the frequencies of the CC genotype of IVS6+95 (rs13290387) in the patients with IS were significantly higher than those in the controls (P = 0·026). After adjusting the confounding risk factors of IS (age, gender, smoking, alcohol drinking, hypertension, diabetes mellitus, and hyperlipidemia) by the multivariate logistic analysis, this significant correlation still remained (P = 0·010).Discussion: The CC genotype of IVS6+95 (rs13290387) was associated with increased incidence of IS in northern Chinese Han populations. This is an initial study to indicate that PAPP-A (rs13290387) might contribute to IS susceptibility in northern Chinese Han populations.

Human annulus cells regulate PAPP-A and IGFBP-4 expression, and thereby insulin-like growth factor bioavailability, in response to proinflammatory cytokine exposure in vitro

Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase which cleaves IGF binding protein (BP)-4 in the extracellular matrix, making IGF available to nearby cells. We have shown that PAPP-A is present in the human intervertebral disc, and is significantly upregulated in more degenerated discs where increased proinflammatory cytokine levels are present. We hypothesized that increased proinflammatory cytokines present in the degenerating disc might be related to PAPP-A expression. Experiments exposed human annulus cells to IL-1-β or TNF-α to test this hypothesis. Treated cells showed significantly increased PAPP-A in conditioned media versus controls (p < 0.001). PAPP-A production following exposure to IL-1β was significantly greater in cells derived from more degenerated versus healthier discs (p = 0.05). PAPP-A gene expression (microarray analysis) was significantly upregulated in IL-1β- or TNF-α-exposed cells (p = 0.01–0.004). Quantitative RT-PCR confirmed significant upregulation of IGFBP-4 in IL-1β- or TNF-α-exposed cells. Data have potential relevance to future cell-based biologic therapies for disc degeneration.

Inducible Knock Out of Pregnancy-Associated Plasma Protein-A Gene Expression in the Adult Mouse: Effect on Vascular Injury Response

Pregnancy-associated plasma protein-A (PAPP-A) enhances local IGF signaling through its ability to proteolyze inhibitory IGF binding proteins. In vivo, PAPP-A (like IGF) appears to exhibit antagonistic pleiotropy; ie, it has beneficial effects early in life but detrimental effects later in life. Accordingly, PAPP-A knockout (KO) mice are born as proportional dwarfs and have diminished reproductive vigor and reduced peak bone mass acquisition at puberty. On the other hand, PAPP-A KO mice live approximately 30% longer than their wild-type littermates, with decreased incidence and severity of age-related diseases and resistance to adverse responses of vascular injury. To be able to distinguish the impact of PAPP-A deficiency in the adult from that in early life, we developed a mouse model suitable for inducible Cre recombinase-mediated excision of the PAPP-A gene. In this study, we characterize the conditional PAPP-A KO mouse model for efficacy of tamoxifen-induced floxed PAPP-A excision in various tissues of adult mice and demonstrate a significant (P = .0001) reduction of neointimal formation in these mice after unilateral carotid artery ligation.

Pregnancy-associated Plasma Protein A (PAPP-A) Modulates the Early Developmental Rate in Zebrafish Independently of Its Proteolytic Activity

Pregnancy-associated plasma protein-A (PAPP-A) is a large metalloproteinase specifically cleaving insulin-like growth factor (IGF) binding proteins, causing increased IGF bioavailability and, hence, local regulation of IGF receptor activation. We have identified two highly conserved zebrafish homologs of the human PAPP-A gene. Expression of zebrafish Papp-a, one of the two paralogs, begins during gastrulation and persists throughout the first week of development, and analyses demonstrate highly conserved patterns of expression between adult zebrafish, humans, and mice. We show that the specific knockdown of zebrafish papp-a limits the developmental rate beginning during gastrulation without affecting the normal patterning of the embryo. This phenotype is different from those resulting from deficiency of Igf receptor or ligand in zebrafish, suggesting a function of Papp-a outside of the Igf system. Biochemical analysis of recombinant zebrafish Papp-a demonstrates conservation of proteolytic activity, specificity, and the intrinsic regulatory mechanism. However, in vitro transcribed mRNA, which encodes a proteolytically inactive Papp-a mutant, recues the papp-a knockdown phenotype as efficiently as wild-type Papp-a. Thus, the developmental phenotype of papp-a knockdown is not a consequence of lacking Papp-a proteolytic activity. We conclude that Papp-a possesses biological functions independent of its proteolytic activity. Our data represent the first evidence for a non-proteolytic function of PAPP-A.

Genetic relationship between serum pregnancy-associated plasma protein-A gene polymorphism and ischemic cerebrovascular disease in a Northern Han Chinese population.

The present study recruited 193 patients with ischemic cerebrovascular disease from Inpatient and Outpatient Departments at the Affiliated Hospital of Qingdao University Medical College, China from August 2008 to May 2010, as well as 120 healthy volunteers from the Medical Examination Center at the Affiliated Hospital of Qingdao University Medical College, China, who served as controls for this study. Patients and control subjects were from the Han population in northern China. Enzyme- linked immunosorbent assay analysis revealed increased levels of serum pregnancy-associated plasma protein-A (PAPP-A) in ischemic cerebrovascular disease patients compared with healthy controls. In addition, the patients exhibited greater frequency of genotype CC and C alleles in a missense A/C (Tyr/Ser) polymorphism (dbSNP: rs7020782) of exon 14 in the PAPP-A gene. Multiple-factor logistic regression analysis on correction of age, gender, history of smoking, hypertension, diabetes mellitus, hypercholesteremia, and ischemic stroke family history showed that the risk for ischemic cerebrovascular disease in the population without the A allele at the A/C genetic locus in exon 14 of the PAPP-A was 2-folds greater than the population expressing the A allele. These experimental findings suggested that ischemic cerebrovascular disease correlated with the C allele in exon 14 of PAPP-A. In addition, the A allele is likely a protective gene; individuals carrying the A allele were less prone to ischemic cerebrovascular disease compared with individuals without the A allele.

Association of pregnancy-associated plasma protein A polymorphism with preeclampsia — A pilot study

Objectives The aim of the study was to investigate genetic and biochemical background of PAPP-A (pregnancy-associated plasma protein A) in patients with risk pregnancies. Design and methods Five PAPP-A gene polymorphisms and PAPP-A maternal serum levels were studied together in 165 women in third trimester pregnancies complicated with threatening preterm labor (n = 98), preeclampsia (n = 35), intrauterine growth restriction (n = 34) and ICP (intrahepatic cholestasis of pregnancy) (n = 15). 114 healthy pregnant women served as controls. Results Preeclamptic patients had significantly higher frequency of TT genotype of Cys327Cys polymorphism compared to controls (p < 0.01). Patients with ICP had increased serum levels of PAPP-A compared to controls and correlation analysis showed significant relationship between PAPP-A and CRP (C-reactive protein) in the patients with intrauterine growth restriction (r = 0.49, p = 0.007). Conclusion Our study indicates the association of TT genotype of Cys327Cys polymorphism of the PAPP-A gene with preeclampsia. However, further study with larger groups of preeclamptic patients is needed to confirm our results.

Relationship of pregnancy-associated plasma protein-A (PAPP-A) gene IVS6+ 95 polymorphism with unstable angina pectoris

ObjectiveTo investigate the association between pregnancy-associated plasma protein-A (PAPP-A) gene IVS6+95 polymorphism and unstable angina pectoris (UAP) in the Chinese Han population of Suwan region.MethodsOne hundred and seventy two patients...

Relationship of pregnancy-associated plasma protein-A (PAPP-A) gene IVS6+ 95 polymorphism with acute coronary syndrome in women

ObjectiveTo investigate the association between the pregnancy-associated plasma protein-A (PAPP-A) gene IVS6+95 polymorphism and acute coronary syndromes (ACS) in women in the Chinese Han population of Suwan region.MethodsOne hundred and...

Association of pregnancy-associated plasma protein-A (PAPP-A) gene IVS6+ 95 polymorphism with acute myocardial infarction

ObjectiveTo investigate the association of pregnancy-associated plasma protein-A (PAPP-A) gene IVS6+95 polymorphism with acute myocardial infarction (AMI) in the Chinese Han population of Sunan region.MethodsTwo hundred and fifty three patients...

Associations of pregnancy-associated plasma protein-A gene IVS6+ 95 polymorphism with acute coronary syndrome

ObjectiveTo investigate the associations of pregnancy-associated plasma protein-A (PAPP-A) gene IVS6+95 polymorphism with the susceptibility of acute coronary syndrome (ACS) in the Chinese Han population of Suwan region.MethodsFour hundred and...

Correlation of the pregnancy-associated plasma protein-A gene IVS6+95 polymorphism with the serum PAPP-A level in patients with acute myocardial infarction

ObjectiveTo investigate the association between PAPP-A gene IVS6+95 polymorphism and the serum level of PAPP-A in patients with AMI from the Chinese Han population of Sunan region.MethodsFifty-six patients with AMI...