Genotype Ser413/Ser ofPAI‐2 polymorphism Ser413/Cys is associated with anti‐phospholipid syndrome and systemic lupus erythematosus in a familial case: comparison with healthy controls

Mercado, Mónica Vázquez-Del; Cobián, Teresa Arcelia García; Valle, José Francisco Muñoz; Torres-Carrillo, Norma; Martín-Márquez, Beatriz Teresita; Arana-Argáez, Víctor; Best-Aguilera, Carlos; Martínez-García, Erika Aurora; Petri, Marcelo H.; Núñez-Atahualpa, Lourdes; Delgado‐Rizo, Vidal

doi:10.1080/03009740601089648

Cited by 18 publications

(11 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These analyses support efforts to understand the regulatory dynamic of SERPINB2 . It is the most highly upregulated gene in inflammatory bowel disease, strongly upregulated in SLE, and sequence variants are associated with multiple human diseases [1, 2, 40, 41]. Our lack of understanding of the regulatory landscape is a significant knowledge gap.…”

Section: 0 Resultsmentioning

confidence: 99%

SERPINB2 is regulated by dynamic interactions with pause-release proteins and enhancer RNAs

Shii

Song

Maurer

et al. 2017

Molecular Immunology

View full text Add to dashboard Cite

The SERPINB2 gene is strongly upregulated in inflammatory states. In monocytes, it can constitute up to 1% of total cellular protein. It functions in protection from proteotoxic stress and plays a role in angioedema. The purpose of this study was to define the roles of enhancer RNAs embedded in the SERPIN gene complex. We found that the upstream enhancer RNAs upregulated SERPINB2 and the enhancer RNAs were expressed prior to those of SERPINB2 mRNA. Studies of the SERPINB2 promoter demonstrated the presence of an RNA polymerase II pause-inducing protein, NELF. Stimulation with LPS led to recruitment of the pause-releasing kinase P-TEFb and departure of the pause-inducing protein NELF. RNA immunoprecipitation revealed that NELF and the CDK9 component of P-TEFb bound to the enhancer RNAs after stimulation with distinct kinetics. Knock-down of the enhancer RNAs compromised stimulus induction of promoter and enhancer chromatin changes. Conversely, over-expression was associated with enhanced recruitment of c-JUN and increased expression of SERPINB2 mRNA expression. This study is the first to associate enhancer RNAs with SERPINB2 and is the first demonstration of acquisition of NELF binding by enhancer RNAs on chromatin.

show abstract

Section: 0 Resultsmentioning

confidence: 99%

SERPINB2 is regulated by dynamic interactions with pause-release proteins and enhancer RNAs

Shii

Song

Maurer

et al. 2017

Molecular Immunology

View full text Add to dashboard Cite

show abstract

“…Although the functional consequences of these residue changes are unknown, several studies have linked PAI-2 genotype and disease. Form A has been associated with lupus erythematosus and thrombic pneumonia in patients with this condition, 117 antiphospholipid syndrome 118 and myocardial infarction, 119,120 although Foy and Grant 121 found no evidence of the link between PAI-2 variants and myocardial infarction. These disease states all relate to disorders in hemostasis, highlighting the role of PAI-2 in this system.…”

Section: Post-transcriptional Controlmentioning

confidence: 98%

Forty Years Later and the Role of Plasminogen Activator Inhibitor Type 2/SERPINB2 Is Still an Enigma

Lee

Cochran

Lobov

et al. 2011

Semin Thromb Hemost

View full text Add to dashboard Cite

Plasminogen activator inhibitor (PAI)-2 expression is acutely upregulated in pregnancy, inflammation, infection, and other pathophysiological conditions. Circumstances that prevent PAI-2 upregulation are associated with chronic pathology. Altogether this strongly suggests that PAI-2 is one of the many proteins that maintain homeostasis during damage or stress. However, several functions ranging from a classical serpin to various intracellular roles have been ascribed to PAI-2 and, because none of these have been definitively proven in vivo, to this day its precise role or roles remains an enigma. This review readdresses the evidence supporting a role for PAI-2 in fibrinolysis and proteolysis within extracellular environments and includes a review of the many potential intracellular functions attributed to PAI-2.

show abstract

“…Candidate gene association studies and gene expression profiling have identified APS susceptibility genes involved in coagulation, inflammation and innate immune response [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. However, and despite some experimental evidences connecting atherosclerosis and aPLA, none of these studies have focused their attention on genes related to atherosclerosis in aPLA carriers.…”

Section: Introductionmentioning

confidence: 99%

LDLR and PCSK9 Are Associated with the Presence of Antiphospholipid Antibodies and the Development of Thrombosis in aPLA Carriers

et al. 2016

View full text Add to dashboard Cite

IntroductionThe identification of the genetic risk factors that could discriminate non- thrombotic from thrombotic antiphospholipid antibodies (aPLA) carriers will improve prognosis of these patients. Several human studies have shown the presence of aPLAs associated with atherosclerotic plaque, which is a known risk factor for thrombosis. Hence, in order to determine the implication of atherosclerosis in the risk of developing thrombosis in aPLA positive patients, we performed a genetic association study with 3 candidate genes, APOH, LDLR and PCSK9.Material & MethodsFor genetic association study we analyzed 190 aPLA carriers -100 with non-thrombotic events and 90 with thrombotic events- and 557 healthy controls. Analyses were performed by χ2 test and were corrected by false discovery rate. To evaluate the functional implication of the newly established susceptibility loci, we performed expression analyses in 86 aPLA carrier individuals (43 with thrombotic manifestations and 43 without it) and in 45 healthy controls.ResultsOur results revealed significant associations after correction in SNPs located in LDLR gene with aPLA carriers and thrombotic aPLA carriers, when compared with healthy controls. The most significant association in LDLR gene was found between SNP rs129083082 and aPLA carriers in recessive model (adjusted P-value = 2.55 x 10−3; OR = 2.18; 95%CI = 1.49–3.21). Furthermore, our work detected significant allelic association after correction between thrombotic aPLA carriers and healthy controls in SNP rs562556 located in PCSK9 gene (adjusted P-value = 1.03 x 10−2; OR = 1.60; 95%CI = 1.24–2.06). Expression level study showed significantly decreased expression level of LDLR gene in aPLA carriers (P-value <0.0001; 95%CI 0.16–2.10; SE 0.38–1.27) in comparison to the control group.DiscussionOur work has identified LDLR gene as a new susceptibility gene associated with the development of thrombosis in aPLA carriers, describing for the first time the deregulation of LDLR expression in individuals with aPLAs. Besides, thrombotic aPLA carriers also showed significant association with PCSK9 gene, a regulator of LDLR plasma levels. These results highlight the importance of atherosclerotic processes in the development of thrombosis in patients with aPLA.

show abstract

Genotype Ser⁴¹³/Ser ofPAI‐2 polymorphism Ser⁴¹³/Cys is associated with anti‐phospholipid syndrome and systemic lupus erythematosus in a familial case: comparison with healthy controls

Abstract: Our data indicate that this family did not follow the Mendelian inheritance pattern. The Ser(413)/Ser genotype demonstrated in 60% of the affected members (3/5) of this family might increase the risk for autoimmune syndromes such as APS or SLE.

Cited by 18 publications

References 20 publications

SERPINB2 is regulated by dynamic interactions with pause-release proteins and enhancer RNAs

SERPINB2 is regulated by dynamic interactions with pause-release proteins and enhancer RNAs

Forty Years Later and the Role of Plasminogen Activator Inhibitor Type 2/SERPINB2 Is Still an Enigma

LDLR and PCSK9 Are Associated with the Presence of Antiphospholipid Antibodies and the Development of Thrombosis in aPLA Carriers

Contact Info

Product

Resources

About