Genetic Variations Linked To Postmenopausal VT

By Mary Ann Moon 

One gene mutation and three single nucleotide polymorphisms have been found linked to an increased risk for nonfatal venous thrombosis in postmenopausal women, according to a report by Nicholas L. Smith, Ph.D., of the University of Washington, Seattle, and associates .

Venous thrombosis (VT) is primarily caused by modifications in the coagulation, anticoagulation, fibrinolysis, and antifibrinolysis pathways that regulate homeostasis.

"Although the roles of pathway proteins and enzymes that activate or inhibit fibrin production and lysis are well characterized, the underlying contribution of genetic variation in these constituents to risk of VT has not been fully identified," noted the investigators.

They studied common genetic variations in 24 candidate genes that are related to blood clotting, using blood samples from subjects in a larger case-control study of VT risk and hormone use.

The case subjects were 349 perimenopausal and postmenopausal women aged 30-89 years who survived an incident deep-vein or pulmonary thrombosis between 1995 and 2003; there were 1,680 control subjects.

Investigators identified one gene (TFPI) with a global association with VT risk, and five single nucleotide polymorphism (SNP) associations across three genes, of which three had not been previously reported.

These variations raised the risk of VT significantly, but not to the degree that the factor V Leiden variant does, they said (JAMA 2007;297:489-98).

The researchers also identified 22 "potentially interesting associations" in 15 other genes that have not been previously recognized as contributing to VT risk. For example, there was "a 24% increase in risk of VT associated with the common thrombomodulin variant, while a recent study examined this variant and reported no significant VT risk."

The researchers also replicated the findings of previous research on a host of genetic variations previously thought to influence VT risk.

Conversely, Dr. Smith and his colleagues failed to find associations between VT risk and a few other genetic variations that have been proposed as risk markers in the literature.

DVT and pulmonary embolism are signifcant contributors to morbidity and mortality in adult women and occur at annual rates of 3-4 per 1,000 person-years among women older than 55 years, according to the authors.

In an editorial comment accompanying this report, Josée Dupuis, Ph.D., of Boston University School of Public Health, and Dr. Christopher J. O'Donnell of the Framingham Heart Study and Harvard Medical School, Boston, said that clinical physicians can expect to encounter an increasing number of articles in the literature "analyzing screens of ever larger numbers of common genetic markers."

A "gold rush" of genomewide association studies is now underway, "using hundreds of thousands of SNPs [to] generate a vast number of potentially valid genetic associations.

"Clinicians and scientists alike will need to exercise care in distinguishing gold from fool's gold when interpreting the results of these studies," Dr. Dupuis and Dr. O'Donnell wrote (JAMA 2007;297:529-32).