Epistatic effect of plasminogen activator inhibitor 1 and β‐Fibrinogen genes on risk of glomerular microthrombosis in lupus nephritis: Interaction with environmental/clinical factors

Gong, Rujun; Liu, Fei; Leishi, LI

doi:10.1002/art.22598

Cited by 21 publications

(27 citation statements)

References 49 publications

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“…HLA, Fcc receptors, complement, TNF, IRF5, STAT 4, BLK-C8orf13, ITGAM-ITGAX and PAI-1 genes have been involved in SLE [20][21][22][23][24][25][26].…”

Section: Discussionmentioning

confidence: 99%

Plasminogen activator inhibitor-1 polymorphisms (−844 G>A and HindIII C>G) in systemic lupus erythematosus: association with clinical variables

et al. 2010

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Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the presence of autoantibodies against nuclear autoantigens as well as cytoplasmic and circulating proteins. Recent studies have demonstrated mechanisms responsible for modulation of the immune response by the plasminogen activator inhibitor-1 (PAI-1). Furthermore, the endogenous PAI-1 has shown to promote a Th2 immune response. We assessed the -844 G>A and HindIII C>G PAI-1 polymorphisms in SLE. In a case-control study of 71 SLE patients classified according to ACR criteria and 71 healthy subjects (HS). The A allele of -844 PAI-1 polymorphism showed a significant difference in SLE patients (41%) when compared with HS (27%) [P = 0.01; OR = 1.8, 95%, CI = 1.1-3.0]. In addition, the -844 G>A PAI-1 polymorphism was associated with increased risk for SLE in a dominant genetic model (G/G vs. G/A + A/A; OR = 2.3, 95% CI = 1.14-4.44). Also, anti-RNP positive antibodies in SLE were associated with G/G -844 PAI-1 genotype. The HindIII polymorphism did not show any differences. The haplotype analysis showed that the AC haplotype confers susceptibility to SLE (OR = 3.1, 95% CI, 1.45-6.52; P = 0.003). The AC haplotype of the -844 and HindIII PAI-1 polymorphism might be an additional susceptibility factor to SLE in Mexicans.

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“…HLA, Fcc receptors, complement, TNF, IRF5, STAT 4, BLK-C8orf13, ITGAM-ITGAX and PAI-1 genes have been involved in SLE [20][21][22][23][24][25][26].…”

Section: Discussionmentioning

confidence: 99%

Plasminogen activator inhibitor-1 polymorphisms (−844 G>A and HindIII C>G) in systemic lupus erythematosus: association with clinical variables

et al. 2010

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“…Samples with equal amounts of total protein (50 mg) were fractionated by 7.5B15% SDS-polyacrylamide gels under reducing conditions and analyzed by western immunoblot as previously described. 26 The antibodies against actin and nonmuscle myosin heavy chain II A (NMHC-IIA) were purchased from Santa Cruz Biotechnology (Santa Cruz, CA) and that for ED-1 from Serotec (Oxford, UK).…”

Section: Cell Culturementioning

confidence: 99%

Inhibiting nonmuscle myosin II impedes inflammatory infiltration and ameliorates progressive renal disease

Jin

Zhuang

et al. 2010

Laboratory Investigation

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The motor protein nonmuscle myosin II (NMII) through its interaction with the actin cytoskeleton constitutes the machinery of cell crawling and has an important role in driving locomotion and infiltration of immune competent cells during inflammatory response and immune reaction. Blebbistatin is a highly selective inhibitor of NMII adenosine triphosphatase. This study examined the effect of NMII inhibition by blebbistatin on inflammation. In vitro, blebbistatin markedly induced actinomyosin complex disassembly in various cultured immunocytes, and functionally impaired their motile activity and invasive capacity as assessed by the Boyden chamber motility assay and the matrigel invasion assay. In vivo, in a rat model of acute inflammation induced by tumor necrosis factor, blebbistatin obliterated renal sequestration of circulating fluorescence-labeled macrophages in a dose-dependent fashion. Moreover, in rats with progressive obstructive nephropathy, blebbistatin treatment exhibited a remarkable renoprotective effect, as evidenced by normalized kidney weight, improved gross morphology, and diminished histologic injury in the tubulointerstitium. This beneficial effect was associated with significant amelioration of renal inflammation, consistent with a primary antiinflammatory action by blebbistatin. In addition, in rats with established obstructive nephropathy, blebbistatin pretreated macrophages showed obliterated recruitment into the inflamed renal parenchyma, denoting that blebbistatin directly impedes inflammatory infiltration by immunocytes. Collectively, our findings suggest that inhibition of NMII has a potent and direct anti-inflammatory effect on the basis of impairment of the actinomyosin powered locomotive machinery, which is essential for migration and infiltration of immune competent cells.

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“…Results can be prioritized based on cross-validation, and only those that meet a preset threshold of predictive ability are considered potential 'true positives.' Crossvalidation methods have been widely used over the last decade in genomic, 41,42 metabolomic, 43 proteomic, 44,45 and transcriptomic 46 -48 studies as a method for discriminating between true associations and false-positive associations.…”

Section: Statisticsmentioning

confidence: 99%

The genetic architecture of fasting plasma triglyceride response to fenofibrate treatment

et al. 2008

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Metabolic response to the triglyceride (TG)-lowering drug, fenofibrate, is shaped by interactions between genetic and environmental factors, yet knowledge regarding the genetic determinants of this response is primarily limited to single-gene effects. Since very low-density lipoprotein (VLDL) is the central carrier of fasting TG, identifying factors that affect both total TG and VLDL -TG response to fenofibrate is critical for predicting individual fenofibrate response. As part of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, 688 individuals from 161 families were genotyped for 91 single-nucleotide polymorphisms (SNPs) in 25 genes known to be involved in lipoprotein metabolism. Using generalized estimating equations to control for family structure, we performed linear modeling to investigate whether single SNPs, single covariates, SNP -SNP interactions, and/or SNP -covariate interactions had a significant association with the change in total fasting TG and fasting VLDL -TG after 3 weeks of fenofibrate treatment. A 10-iteration fourfold cross-validation procedure was used to validate significant associations and quantify their predictive abilities. More than one-third of the significant, cross-validated SNP -SNP interactions predicting each outcome involved just five SNPs, showing that these SNPs are of key importance to fenofibrate response. Multiple variable models constructed using the top-ranked SNPcovariate interactions explained 11.9% more variation in the change in TG and 7.8% more variation in the change in VLDL than baseline TG alone. These results yield insight into the complex biology of fenofibrate response, which can be used to target fenofibrate therapy to individuals who are most likely to benefit from the drug.

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Epistatic effect of plasminogen activator inhibitor 1 and β‐Fibrinogen genes on risk of glomerular microthrombosis in lupus nephritis: Interaction with environmental/clinical factors

Cited by 21 publications

References 49 publications

Plasminogen activator inhibitor-1 polymorphisms (−844 G>A and HindIII C>G) in systemic lupus erythematosus: association with clinical variables

Plasminogen activator inhibitor-1 polymorphisms (−844 G>A and HindIII C>G) in systemic lupus erythematosus: association with clinical variables

Inhibiting nonmuscle myosin II impedes inflammatory infiltration and ameliorates progressive renal disease

The genetic architecture of fasting plasma triglyceride response to fenofibrate treatment

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