Nicholas J. Leeper
Genes that determine height may also play a role in the formation of varicose veins, with taller people at greater risk for developing the condition, according to a study published in Circulation.
“This study is the largest study ever conducted aimed at identifying the root causes of varicose vein disease, including data on almost half a million individuals,” Nicholas J. Leeper, MD, associate professor of cardiovascular medicine and vascular surgery and chief of vascular medicine at Stanford University, told Cardiology Today. “It included a large genetic analysis along with classical risk factor prediction studies and identified a number of new risk factors for this highly prevalent condition. One of the major new findings of the study is that height is a strong predictor of risk for varicose veins, and that the genes underlying height seem to predispose to the development of this vascular disorder.”
To identify risk factors for varicose vein disease, researchers used data from the UK Biobank, which collected information related to demographics, socioeconomics, lifestyle behaviors, medical history, phenotype and genetics between 2006 and 2010 (n = 413,519; mean age, 58 years; 54% women; mean height, 168 cm; 2% with history of deep vein thrombosis).
Researchers used machine learning — or a gradient machine boosting model — to search for risk factors. Univariable and multivariable Cox regression analyses were then used to further investigate the associations of traditional varicose vein risk factors and the top 10 predictors identified through the search. Researchers adjusted for age, sex and previously known varicose vein risk factors (BMI, waist-hip ratio, history of DVT and pregnancy).
Next, researchers performed a genome-wide association study of varicose veins on 337,536 controls unrelated to the other participants (9,577 cases).
Known risk factors for varicose vein disease, including age, sex, obesity, pregnancy and history of DVT, were confirmed. Leg bioimpedance, surgery on leg arteries and height were newly identified as risk factors. Researchers found that, after adjusting for traditional risk factors, greater height was independently associated with varicose veins (HR = 1.74; 95% CI, 1.51-2.01).
After observing the strong association between height and varicose veins, researchers performed multiple Mendelian randomization analyses to examine whether there is a causal role for height in the development of varicose veins and found that increased height is causally related to varicose veins (OR = 1.26; P = 2.07 x 10-16).
The genome-wide association study showed a genetic correlation between height and varicose veins, with a 16% overlap between height and varicose veins. This is larger than the estimated genetic correlation with BMI and waist-hip ratio, according to the researchers. History of DVT had the greatest genetic correlation with varicose vein disease.
“We now have a much better understanding of what drives disease, and how to predict it in at-risk individuals,” Leeper said. “We hope to leverage the new knowledge about the genetic pathways that are associated with disease to develop the first medical therapy for varicose veins, a condition which currently can only be treated with compression stockings or surgical interventions aimed at removing the veins themselves.”
Insight into clinical features
In a related editorial, Quinn S. Wells, MD, PharmD, MSc, of the department of medicine at Vanderbilt University Medical Center, wrote: “One innovative aspect of the study was the use of unsupervised machine learning for agnostic interrogation of over 2,700 diverse clinical variables to identify those associated with incident varicose veins. This approach identified established risk factors such as increasing age, obesity and history of DVT as well as a number of novel candidate risk factors including increased height and leg bioimpedance, both of which remained independently associated with varicose vein risk when evaluated using conventional statistical models. This analysis also provided insight into clinical features whose associations with varicose veins were ambiguous due to conflicting data from prior reports, for example identifying systolic blood pressure as a likely risk factor but detecting no increased risk with oral contraceptive use.” – by Melissa J. Webb
For more information:
Nicholas J. Leeper, MD, can be reached at firstname.lastname@example.org.
Disclosures: The authors and Wells report no relevant financial disclosures.