Polymorphisms at LDLR locus may be associated with coronary artery disease through modulation of coagulation factor VIII activity and independently from lipid profile

Martinelli, Nicola; Girelli, Domenico; Lunghi, Barbara; Pinotti, Mirko; Marchetti, Giovanna; Malerba, Giovanni; Pignatti, Pier Franco; Corrocher, Roberto; Olivieri, Oliviero; Bernardi, Francesco

doi:10.1182/blood-2010-03-277079

Cited by 90 publications

(91 citation statements)

References 49 publications

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“…More recent evidence shows that these plasma hemostatic proteins are also risk factors for other cardiovascular diseases (CVD) [4][5][6][7][8]. The broader role of FVIII and vWF is further supported by studies showing that genetic factors modulating the variability of these proteins are also associated with CVD.…”

Section: Introductionmentioning

confidence: 69%

Combined Analysis of Three Genome-Wide Association Studies on vWF and FVIII Plasma Levels

Antoni¹,

Oudot-Mellakh²,

Dimitromanolakis³

et al. 2014

Bioinformatics

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Background: Elevated levels of factor VIII (FVIII) and von Willebrand Factor (vWF) are well-established risk factors for cardiovascular diseases, in particular venous thrombosis. Although high, the heritability of these traits is poorly explained by the genetic factors known so far. The aim of this work was to identify novel single nucleotide polymorphisms (SNPs) that could influence the variability of these traits. Methods: Three independent genome-wide association studies for vWF plasma levels and FVIII activity were conducted and their results were combined into a meta-analysis totalling 1,624 subjects.

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Section: Introductionmentioning

confidence: 69%

Combined Analysis of Three Genome-Wide Association Studies on vWF and FVIII Plasma Levels

Antoni¹,

Oudot-Mellakh²,

Dimitromanolakis³

et al. 2014

Bioinformatics

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“…We observed alteration in methylation patterns in genes previously associated with obesity and cardiovascular disease pathogenesis: stable methylation of MMP9 in PBLs, which has been associated with increased BMI in obese adults [45]; promoter hypermethylation of LDLR observed in patients with atherosclerosis [46] and for which genome-wide association studies have shown polymorphisms in individuals with coronary artery disease [47] and hypermethylation of GCK [48], FOXP1, MACROD2, JARID2, ZMIZ1 and the Genes were identified by bump hunting using a 1 kb window a Genes that also have DML maternally imprinted gene, KCNQ1 [49], as a predictor for type 2 diabetes susceptibility. The agreement between our results and those of previous studies suggests that altered methylation of metabolically relevant genes may be one mechanism by which IUGR leads to increased susceptibility to metabolic disease.…”

Section: Discussionmentioning

confidence: 99%

DNA hypermethylation of CD3+ T cells from cord blood of infants exposed to intrauterine growth restriction

et al. 2016

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Aims/hypothesis Intrauterine growth restriction (IUGR) is associated with increased susceptibility to obesity, metabolic syndrome and type 2 diabetes. Although the mechanisms underlying the developmental origins of metabolic disease are poorly understood, evidence suggests that epigenomic alterations play a critical role. We sought to identify changes in DNA methylation patterns that are associated with IUGR in CD3 + T cells purified from umbilical cord blood obtained from male newborns who were appropriate for gestational age (AGA) or who had been exposed to IUGR. Methods CD3 + T cells were isolated from cord blood obtained from IUGR and AGA infants. The genome-wide methylation profile in eight AGA and seven IUGR samples was determined using the HELP tagging assay. Validation analysis using targeted bisulfite sequencing and bisulfite massARRAY was performed on the original cohort as well as biological replicates consisting of two AGA and four IUGR infants. The Segway algorithm was used to identify methylation changes within regulatory regions of the genome. Results A global shift towards hypermethylation in IUGR was seen compared with AGA (89.8% of 4,425 differentially methylated loci), targeted to regulatory regions of the genome, specifically promoters and enhancers. Pathway analysis identified dysregulation of pathways involved in metabolic disease (type 2 diabetes mellitus, insulin signalling, mitogen-activated protein kinase signalling) and T cell development, regulation and activation (T cell receptor signalling), as well as transcription factors (TCF3, LEF1 and NFATC) that regulate T cells. Furthermore, bump-hunting analysis revealed differentially methylated regions in PRDM16 and HLA-DPB1, genes important for adipose tissue differentiation, stem cell maintenance and function and T cell activation. Conclusions/interpretation Our findings suggest that the alterations in methylation patterns observed in IUGR CD3 + T cells may have functional consequences in targeted genes, regulatory regions and transcription factors. These may serve as biomarkers to identify those at 'high risk' for diminished attainment of full health potential who can benefit from early interventions.

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“…Furthermore, inhibition of both receptors by their highly specific ligand ␣-2-macroglobulin receptor-associated protein (RAP) (3,4) increased its half-life in mice (5,6). In humans, polymorphism in either LDLR or LRP is associated with elevated levels of FVIII (7)(8)(9)(10).…”

Section: Factor VIII (Fviii)mentioning

confidence: 99%

Mapping the Binding Region on the Low Density Lipoprotein Receptor for Blood Coagulation Factor VIII

Kurasawa

Shestopal

Karnaukhova

et al. 2013

Journal of Biological Chemistry

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Background: Low density lipoprotein receptor (LDLR) mediates clearance of blood coagulation factor VIII (FVIII). Results:The region of complement-type repeats 2-5 in LDLR was identified as the binding site for FVIII and for ␣-2-macroglobulin receptor-associated protein (RAP). Conclusion: Binding sites of LDLR for FVIII, and also for RAP, were characterized. Significance: This provides new data on LDLR structure and function and on FVIII catabolism.

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Polymorphisms at LDLR locus may be associated with coronary artery disease through modulation of coagulation factor VIII activity and independently from lipid profile

Cited by 90 publications

References 49 publications

Combined Analysis of Three Genome-Wide Association Studies on vWF and FVIII Plasma Levels

Combined Analysis of Three Genome-Wide Association Studies on vWF and FVIII Plasma Levels

DNA hypermethylation of CD3+ T cells from cord blood of infants exposed to intrauterine growth restriction

Mapping the Binding Region on the Low Density Lipoprotein Receptor for Blood Coagulation Factor VIII

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