Leiden, the Netherlands - Researchers in the Netherlands have unearthed seven single-nucleotide polymorphisms (SNPs) associated with deep vein thrombosis (DVT) in three large, well-characterized case-control studies. The evidence was strongest for three of the seven, which interestingly are all in or near genes that have a clear role in blood coagulation.

Dr Irene D Bezemer (Leiden University Medical Center, the Netherlands) and colleagues report their findings in the March 19, 2008 issue of the Journal of the American Medical Association [1]. "Although most variants had a modest effect on risk, they were common and could therefore be responsible for as many thrombotic events in the population as stronger but rarer variants," they note. However, they add that more work will be needed to further knowledge about these issues.

In an accompanying editorial [2], Dr Edwin G Bovill (University of Vermont College of Medicine, Burlington) says: "The authors cast a broad net . . . including nearly half the known genes in the human genome." The most important observations "are the high prevalence of the risk alleles and evidence of genetic dosage, with higher odds ratios for thrombosis in homozygotes vs heterozygotes," he notes.

Bezemer et al explain that family and twin studies show that genetics account for about 60% of the risk for DVT. Although deficiencies in natural anticoagulants, such as antithrombin, protein C, and protein S, have been identified, the variants causing these deficiencies are rare, accounting for only about 1% of all DVTs. Two more common genetic variants, factor V Leiden and prothrombin G20210A, have also been consistently found to be associated with DVT "but still only explain a fraction of the DVT events."

Hence, they set out to try to identify other common gene variants associated with DVT. Using three large case-control studies of first DVT—the Leiden Thrombophilia Study (LETS) and the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA-1 and MEGA-2 studies)—they investigated whether any of 19 682 SNPs were associated with DVT in 3155 cases and 5087 controls. They selected SNPs on the basis of their potential to affect gene function or expression and, on average, analyzed fewer than two SNPs per gene.

The three SNPs with the strongest association with DVT were in the genes for antithrombin (SERPINC1), the platelet collagen receptor (GP6), and a gene in the cytochrome P450 family (CYP4V2). All three were common in the population studied, with allele frequencies ranging from 0.10 to 0.84 and relatively weak additive odds ratios ranging from 1.15 to 1.29.

The attributable risk associated with GP6 is similar to that for factor V Leiden—one of the most commonly ordered genetic tests.

In his editorial, Bovill attempts to put the findings into perspective, using the example of the risk associated with homozygosity for GP6: "To put this into the context of clinical testing for venous thrombosis risk factors, the attributable risk associated with GP6 is similar to that for factor V Leiden—one of the most commonly ordered genetic tests—and much greater than for protein C, protein S, or antithrombin," he notes. However, he cautions that newly identified risk factors, such as GP6, "must be validated in well-designed clinical studies to define their clinical utility."

The researchers agree. "The associations between SNPs and DVT were modest . . . [but] clinical utility may stem from the determinants being frequent and affecting many people, as well as from interactions with environmental risk factors and interactions with other genes. Subsequent studies will be needed to further our knowledge on these issues," they conclude.