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Meta-Analysis Implicates Two New Loci in Venous Thromboembolism

NEW YORK (GenomeWeb) – A GWAS meta-analysis published online today in the American Journal of Human Genetics led to variants in two new genes that appear to contribute to venous thromboembolism, a group of blood clot conditions that include deep vein thrombosis and pulmonary embolism.

An international team that included members of the International Network against Thrombosis (INVENT) did a meta-analysis of data from a dozen prior GWAS involving more than 7,500 individuals with venous thromboembolism and tens of thousands of unaffected controls. Along with loci linked to the disease in the past, the search led to venous thromboembolism-associated variants in TSPAN15 and SLC44A2 — sites replicated through testing on thousands more affected and unaffected individuals.

While the non-synonymous SNP in the latter gene has been implicated in forms of lung injury that can occur after blood transfusion, the study's authors noted that "TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers."

Still, they maintained that findings from the meta-analysis "pave the way for novel mechanistic concepts of [venous thromboembolism] pathophysiology, new biomarkers for the disease, and novel therapeutic perspectives."

Although environmental factors such as endothelial injury can contribute to venous thromboembolism, risk of the blood clot disease is known to be higher in individuals with affected family members, suggesting it has heritable components as well.

Genetic factors already linked to the condition include rare alterations affecting blood coagulation inhibitors, the researchers noted. But more common variants and non-"O" blood types have also been implicated in venous thromboembolism as well.

To search for still other risk variants, the team considered genotype patterns at more than 6.7 million SNPs in 7,507 individuals with venous thromboembolism and 52,632 without — cases and controls who had been tested through 12 previous GWAS.

When they scanned for variants that were over-represented in cases compared to controls, the researchers tracked down SNPs in and around half a dozen genes linked to venous thromboembolism in the past: VTE, F2, F5, F11, FGG, and PROCR.

They also identified three new candidate variants, validating associations for SNPs in TSPAN15 and SLC44A2 through follow-up testing on more than 3,000 individuals with venous thromboembolism and nearly 2,600 unaffected individuals enrolled through three more case-control studies.

The team has yet to untangle the mechanism by which TSPAN15 and SLC44A2 may contribute to venous thromboembolism risk.

Follow-up experiments in 10 tissue types suggest that variants in linkage disequilibrium with associated SNOs may affect methylation and/or expression of TSPAN15 and SLC44A2 in specific blood cell types, though the researchers noted that more research is needed to explore such potential regulatory links.

Those involved in the study speculated that there are likely other common variants that make more modest contributions to venous thromboembolism risk. In particular, they argued that even larger studies are needed to dig into SNPs showing suggestive ties to venous thromboembolism that did not reach statistical significance in the current analysis.