Clinical and Genetic Determinants of Varicose Veins: Prospective, Community-Based Study of ≈500 000 Individuals

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.

[1]  Mei-Ching Lee,et al.  Association of Varicose Veins With Incident Venous Thromboembolism and Peripheral Artery Disease , 2018, JAMA.

[2]  Erdogan Taskesen,et al.  Functional mapping and annotation of genetic associations with FUMA , 2017, Nature Communications.

[3]  J. Sundquist,et al.  Body Height and Incident Risk of Venous Thromboembolism: A Cosibling Design , 2017, Circulation. Cardiovascular genetics.

[4]  J. Fareed,et al.  Do blood constituents in varicose veins differ from the systemic blood constituents? , 2015, European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery.

[5]  P. Elliott,et al.  UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age , 2015, PLoS medicine.

[6]  Ross M. Fraser,et al.  Genetic studies of body mass index yield new insights for obesity biology , 2015, Nature.

[7]  J. Hirschhorn,et al.  Biological interpretation of genome-wide association studies using predicted gene functions , 2015, Nature Communications.

[8]  Carson C Chow,et al.  Second-generation PLINK: rising to the challenge of larger and richer datasets , 2014, GigaScience.

[9]  M. Daly,et al.  LD Score regression distinguishes confounding from polygenicity in genome-wide association studies , 2014, Nature Genetics.

[10]  Ross M. Fraser,et al.  Defining the role of common variation in the genomic and biological architecture of adult human height , 2014, Nature Genetics.

[11]  N. Yuldasheva,et al.  Piezo1 integration of vascular architecture with physiological force , 2014, Nature.

[12]  J. Sundquist,et al.  Venous Thromboembolism and Varicose Veins Share Familial Susceptibility: A Nationwide Family Study in Sweden , 2014, Journal of the American Heart Association.

[13]  Fatimah Ibrahim,et al.  The Theory and Fundamentals of Bioimpedance Analysis in Clinical Status Monitoring and Diagnosis of Diseases , 2014, Sensors.

[14]  Alois Knoll,et al.  Gradient boosting machines, a tutorial , 2013, Front. Neurorobot..

[15]  Ellen T. Gelfand,et al.  The Genotype-Tissue Expression (GTEx) project , 2013, Nature Genetics.

[16]  A. Hamdan.  Management of varicose veins and venous insufficiency. , 2012, JAMA.

[17]  J. Szecsenyi,et al.  Varicose veins are a risk factor for deep venous thrombosis in general practice patients. , 2012, VASA. Zeitschrift fur Gefasskrankheiten.

[18]  A. Davies,et al.  A review of familial, genetic, and congenital aspects of primary varicose vein disease. , 2012, Circulation. Cardiovascular genetics.

[19]  A. V. Van rij,et al.  Evidence for a genetic role in varicose veins and chronic venous insufficiency , 2012, Phlebology.

[20]  Thomas Meitinger,et al.  Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution , 2010, Nature Genetics.

[21]  T. Luukkaala,et al.  Effect of family history on the risk of varicose veins is affected by differential misclassification. , 2010, Journal of clinical epidemiology.

[22]  Andrew D. Johnson,et al.  Genome-wide association study of blood pressure and hypertension , 2009, Nature Genetics.

[23]  C. Fegan,et al.  Higher prevalence of thrombophilia in patients with varicose veins and venous ulcers than controls. , 2009, Journal of vascular surgery.

[24]  T. Luukkaala,et al.  Persons With Varicose Veins Have a High Subsequent Incidence of Arterial Disease: A Population-Based Study in Tampere, Finland , 2007, Angiology.

[25]  G. Schmid-Schönbein,et al.  Chronic venous disease. , 2006, Minerva cardioangiologica.

[26]  Monte M Winslow,et al.  Calcineurin/NFAT signaling in osteoblasts regulates bone mass. , 2006, Developmental cell.

[27]  S. Tognazzo,et al.  The overlapping of local iron overload and HFE mutation in venous leg ulcer pathogenesis. , 2006, Free radical biology & medicine.

[28]  J. Beebe-Dimmer,et al.  The epidemiology of chronic venous insufficiency and varicose veins. , 2005, Annals of epidemiology.

[29]  H. Maricq,et al.  Prevalence, risk factors, and clinical patterns of chronic venous disorders of lower limbs: a population-based study in France. , 2004, Journal of vascular surgery.

[30]  P. Vokonas,et al.  Are Varicose Veins a Marker for Susceptibility to Coronary Heart Disease in Men? Results from the Normative Aging Study , 2004, Annals of vascular surgery.

[31]  A. Busjahn,et al.  Heritability of Venous Function in Humans , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[32]  P. Allan,et al.  Lifestyle factors and the risk of varicose veins: Edinburgh Vein Study. , 2003, Journal of clinical epidemiology.

[33]  Feng Chen,et al.  Signals Transduced by Ca2+/Calcineurin and NFATc3/c4 Pattern the Developing Vasculature , 2001, Cell.

[34]  A. Joyner,et al.  Identification and characterization of Lbh, a novel conserved nuclear protein expressed during early limb and heart development. , 2001, Developmental biology.

[35]  M. Alhenc-Gelas,et al.  Thrombomodulin Promoter Mutations, Venous Thrombosis, and Varicose Veins , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[36]  F. Berrino,et al.  High endogenous estradiol is associated with increased venous distensibility and clinical evidence of varicose veins in menopausal women. , 2000, Journal of vascular surgery.

[37]  C. Abbott,et al.  Mutations in Sox18 underlie cardiovascular and hair follicle defects in ragged mice , 2000, Nature Genetics.

[38]  T. Baglin,et al.  Risk of venous thromboembolism associated with the common hereditary haemochromatosis Hfe gene (C282Y) mutation , 1999, British journal of haematology.

[39]  E. Schwartz,et al.  Prevalence of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation in patients with varicose veins of lower limbs. , 1998, Molecular genetics and metabolism.

[40]  D. Milewicz,et al.  Fibrillin–2 (FBN2) mutations result in the Marfan–like disorder, congenital contractural arachnodactyly , 1995, Nature Genetics.

[41]  W. Lamorte,et al.  Risk factors for chronic venous insufficiency: a dual case-control study. , 1995, Journal of vascular surgery.

[42]  A. Reunanen,et al.  Prevalence and risk factors of varicose veins in lower extremities: mini-Finland health survey. , 1995, The European journal of surgery = Acta chirurgica.

[43]  I. de Vincenzi,et al.  Importance of the familial factor in varicose disease. Clinical study of 134 families. , 1994, The Journal of dermatologic surgery and oncology.

[44]  S. Komşuoğlu,et al.  Prevalence and risk factors of varicose veins in an elderly population. , 1994, Gerontology.

[45]  S. Fukuda,et al.  Mucopolysaccharidosis type IVA. N-acetylgalactosamine-6-sulfate sulfatase exonic point mutations in classical Morquio and mild cases. , 1992, The Journal of clinical investigation.

[46]  M. Hirai,et al.  Prevalence and Risk Factors of Varicose Veins in Japanese Women , 1990, Angiology.

[47]  A L Dannenberg,et al.  The epidemiology of varicose veins: the Framingham Study. , 1988, American journal of preventive medicine.

[48]  J. Abramson,et al.  The epidemiology of varicose veins. A survey in western Jerusalem. , 1981, Journal of epidemiology and community health.

[49]  S. Malhotra.  An epidemiological study of varicose veins in Indian railroad workers from the South and North of India, with special reference to the causation and prevention of varicose veins. , 1972, International journal of epidemiology.