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Extracellular matrix remodelling in response to venous hypertension: proteomics of human varicose veins.

ABSTRACT: Extracellular matrix remodelling has been implicated in a number of vascular conditions, including venous hypertension and varicose veins. However, to date, no systematic analysis of matrix remodelling in human veins has been performed.To understand the consequences of venous hypertension, normal and varicose veins were evaluated using proteomics approaches targeting the extracellular matrix. Varicose saphenous veins removed during phlebectomy and normal saphenous veins obtained during coronary artery bypass surgery were collected for proteomics analysis. Extracellular matrix proteins were enriched from venous tissues. The proteomics analysis revealed the presence of >150 extracellular matrix proteins, of which 48 had not been previously detected in venous tissue. Extracellular matrix remodelling in varicose veins was characterized by a loss of aggrecan and several small leucine-rich proteoglycans and a compensatory increase in collagen I and laminins. Gene expression analysis of the same tissues suggested that the remodelling process associated with venous hypertension predominantly occurs at the protein rather than the transcript level. The loss of aggrecan in varicose veins was paralleled by a reduced expression of aggrecanases. Chymase and tryptase ?1 were among the up-regulated proteases. The effect of these serine proteases on the venous extracellular matrix was further explored by incubating normal saphenous veins with recombinant enzymes. Proteomics analysis revealed extensive extracellular matrix degradation after digestion with tryptase ?1. In comparison, chymase was less potent and degraded predominantly basement membrane-associated proteins.The present proteomics study provides unprecedented insights into the expression and degradation of structural and regulatory components of the vascular extracellular matrix in varicosis.

SUBMITTER: Barallobre-Barreiro J

PROVIDER: S-EPMC4872879 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Extracellular matrix remodelling in response to venous hypertension: proteomics of human varicose veins.

Barallobre-Barreiro Javier J Oklu Rahmi R Lynch Marc M Fava Marika M Baig Ferheen F Yin Xiaoke X Barwari Temo T Potier David N DN Albadawi Hassan H Jahangiri Marjan M Porter Karen E KE Watkins Michael T MT Misra Sanjay S Stoughton Julianne J Mayr Manuel M

Cardiovascular research 20160411 3

<h4>Aims</h4>Extracellular matrix remodelling has been implicated in a number of vascular conditions, including venous hypertension and varicose veins. However, to date, no systematic analysis of matrix remodelling in human veins has been performed.<h4>Methods and results</h4>To understand the consequences of venous hypertension, normal and varicose veins were evaluated using proteomics approaches targeting the extracellular matrix. Varicose saphenous veins removed during phlebectomy and normal ...[more]

PMID: 27068509

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Project description:Varicose veins are common but rarely associated with serious health risks. Deep venous thrombosis (DVT), pulmonary embolism (PE), and peripheral artery disease (PAD) are also vascular diseases but associated with serious systemic effects. Little is known about the association between varicose veins and the incidence of other vascular diseases including DVT, PE, and PAD.To investigate whether varicose veins are associated with an increased risk of DVT, PE, or PAD.A retrospective cohort study using claims data from Taiwan's National Health Insurance program. Patients aged 20 years and older with varicose veins were enrolled from January 1, 2001-December 31, 2013, and a control group of patients without varicose veins were matched by propensity score. Patients previously diagnosed with DVT, PE, or PAD were excluded. Follow-up ended December 31, 2014.Presence of varicose veins.Incidence rates of DVT, PE, and PAD were assessed in people with and without varicose veins. Cox proportional hazards models were used to estimate relative hazards, with the control group as reference.There were 212?984 patients in the varicose veins group (mean [SD] age, 54.5 [16.0] years; 69.3% women) and 212?984 in the control group (mean [SD] age, 54.3 [15.6] years; 70.3% women). The median follow-up duration was 7.5 years for DVT, 7.8 years for PE, and 7.3 years for PAD for patients with varicose veins, and for the control group, follow-up duration was 7.6 years for DVT, 7.7 years for PE, and 7.4 years for PAD. The varicose veins group had higher incidence rates than the control group for DVT (6.55 vs 1.23 per 1000 person-years [10?360 vs 1980 cases]; absolute risk difference [ARD], 5.32 [95% CI, 5.18-5.46]), for PE (0.48 for the varicose veins group vs 0.28 for the control group per 1000 person-years [793 vs 451 cases]; ARD, 0.20 [95% CI, 0.16-0.24]), and for PAD (10.73 for the varicose veins group vs 6.22 for the control group per 1000 person-years [16?615 vs 9709 cases]; ARD, 4.51 [95% CI, 4.31-4.71]). The hazard ratios for the varicose veins group compared with the control group were 5.30 (95% CI, 5.05-5.56) for DVT, 1.73 (95% CI, 1.54-1.94) for PE, and 1.72 (95% CI, 1.68-1.77) for PAD.Among adults diagnosed with varicose veins, there was a significantly increased risk of incident DVT; the findings for PE and PAD are less clear due to the potential for confounding. Whether the association between varicose veins and DVT is causal or represents a common set of risk factors requires further research.

Project description:BackgroundVaricose veins are found to be associated with increased risk of venous thromboembolism (VTE) in many observational studies, but whether varicose veins are causally associated with VTE remains unclear. Therefore, we used a series of Mendelian randomization (MR) methods to investigate that association.Methods23 independent single-nucleotide polymorphisms (SNPs) for varicose veins were obtained from the Pan UK Biobank analysis. The outcomes datasets for deep vein thrombosis (DVT), pulmonary embolism (PE) and venous thromboembolism (VTE) were obtained from the FinnGen study. Before analysis, body mass index (BMI) and height were included as confounders in our MR model. Basic MR [inverse-variance weighted (IVW), weight-median, penalized weighted-median and MR-Egger methods] and MR-PRESSO were performed against each outcome using the whole SNPs and SNPs after excluding those associated with confounders. If causal associations were suggested for any outcome, a basic MR validation analysis, a multivariable MR analysis with BMI and height, a Causal Analysis Using Summary Effect estimates (CAUSE), and a two-step MR analysis with BMI and height, would follow.ResultsUsing 21 qualified SNPs, the IVW method (OR: 1.173, 95% CI: 1.070-1.286, p < 0.001, FDR = 0.002), the weighted median method (OR: 1.255, 95% CI: 1.106-1.423, p < 0.001, FDR = 0.001), the penalized weighted median method (OR: 1.299, 95% CI: 1.128-1.495, p < 0.001, FDR = 0.001) and the MR-PRESSO (OR: 1.165, 95% CI: 1.067-1.273, p = 0.003, FDR = 0.009) suggested potential causal effect of varicose veins on DVT, but no cause effect was found for PE and VTE. Excluding SNPs associated with confounders yielded similar results. The causal association with DVT was validated using a self-reported DVT cohort (IVW, OR: 1.107, 95% CI: 1.041-1.178, p = 0.001). The causal association maintained after adjustment for height (OR = 1.105, 95% CI: 1.028-1.188, p = 0.007), BMI (OR = 1.148, 95% CI: 1.059-1.244, p < 0.001) and them both (OR = 1.104, 95% CI: 1.035-1.177, p = 0.003). The causal association also survived the strict CAUSE (p = 0.018). Finally, in two-step MR, height and BMI were found to have causal effects on both varicose veins and DVT.ConclusionGenetically predicted varicose veins may have a causal effect on DVT and may be one of the mediators of obesity and taller height that predispose to DVT.

Project description:BACKGROUND:Varicose veins are a common problem with no approved medical therapies. Although it is believed that varicose vein pathogenesis is multifactorial, there is limited understanding of the genetic and environmental factors that contribute to their formation. Large-scale studies of risk factors for varicose veins may highlight important aspects of pathophysiology and identify groups at increased risk for disease. METHODS:We applied machine learning to agnostically search for risk factors of varicose veins in 493?519 individuals in the UK Biobank. Predictors were further studied with univariable and multivariable Cox regression analyses (2441 incident events). A genome-wide association study of varicose veins was also performed among 337?536 unrelated individuals (9577 cases) of white British descent, followed by expression quantitative loci and pathway analyses. Because height emerged as a new candidate risk factor, we performed mendelian randomization analyses to assess a potential causal role for height in varicose vein development. RESULTS:Machine learning confirmed several known (age, sex, obesity, pregnancy, history of deep vein thrombosis) and identified several new risk factors for varicose vein disease, including height. After adjustment for traditional risk factors in Cox regression, greater height remained independently associated with varicose veins (hazard ratio for upper versus lower quartile, 1.74; 95% CI, 1.51-2.01; P<0.0001). A genome-wide association study identified 30 new genome-wide significant loci, identifying pathways involved in vascular development and skeletal/limb biology. Mendelian randomization analysis provided evidence that increased height is causally related to varicose veins (inverse-variance weighted: odds ratio, 1.26; P=2.07×10-16). CONCLUSIONS:Using data from nearly a half-million individuals, we present a comprehensive genetic and epidemiological study of varicose veins. We identified novel clinical and genetic risk factors that provide pathophysiological insights and could help future improvements of treatment of varicose vein disease.

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Dataset Information

Extracellular matrix remodelling in response to venous hypertension: proteomics of human varicose veins.

Publications

Extracellular matrix remodelling in response to venous hypertension: proteomics of human varicose veins.

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