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Clinical and Genetic Determinants of Varicose Veins Prospective, Community-Based Study of approximate to 500 000 Individuals
Stanford Univ, Sch Med, Dept Surg, Div Vasc Surg, Stanford, CA 94305 USA.
Stanford Univ, Sch Med, Dept Surg, Div Vasc Surg, Stanford, CA 94305 USA.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.ORCID iD: 0000-0001-5894-0351
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2018 (English)In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 138, no 25, p. 2869-2880Article in journal (Refereed) Published
Abstract [en]

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% Cl, 1.51-2.01; P<0.0001). A genomewide 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=2.07x10(-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.

Place, publisher, year, edition, pages
2018. Vol. 138, no 25, p. 2869-2880
Keywords [en]
epidemiology, genetics, genome-wide association study, varicose veins
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:uu:diva-374122DOI: 10.1161/CIRCULATIONAHA.118.035584ISI: 000453713500067PubMedID: 30566020OAI: oai:DiVA.org:uu-374122DiVA, id: diva2:1281982
Funder
Knut and Alice Wallenberg Foundation, 2013.0126Available from: 2019-01-23 Created: 2019-01-23 Last updated: 2019-01-23Bibliographically approved

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Lindholm, Daniel PGustafsson, Stefan

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CardiologyUCR-Uppsala Clinical Research CenterScience for Life Laboratory, SciLifeLabMolecular epidemiology
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