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U of Chicago Researchers Discover Novel Polymorphisms Associated With VTE in African Americans

NEW YORK (GenomeWeb) – A research team led by University of Chicago researchers has discovered novel polymorphisms on chromosome 20 associated with increased risk of venous thromboembolism (VTE) in populations of African descent.

VTE is a disorder characterized by blood clots that form in the deep veins of the legs. These clots can travel to the lungs and become fatal. Those who suffer from VTE often have one or several alterations in their DNA that affect normal function of blood's clotting process.

In a study published today in Blood, the researchers found that the one-size-fits-all approach to identifying these genetic variants does not serve minority populations.

"While African Americans have a high risk for VTE, previous studies have not specifically focused on this population," senior study author Minoli Perera of the University of Chicago said in a statement. "If we are not looking for the correct genetic mutations when we run a laboratory test, we are doing a disservice to minority populations."

Perera's team conducted a genome-wide association study to understand the genetic risk factors for VTE specific to African Americans. They genotyped DNA samples from 578 African Americans, 146 of whom had a history of unprovoked VTE.

This first cohort of subjects underwent genotyping through two projects: the International Warfarin Pharmacogenetics Consortium and the DC Prostate Cancer Study. The first group (88 patients) was genotyped using the Illumina 610 Quad BeadChip, and the second group (344 patients) was genotyped using the Illumina Infinium Human 1M-Duo. Since different genotyping platforms were used, the researchers ensured that each dataset underwent rigorous quality control filters individually and then as a merged dataset.

The dataset from this cohort were meta-analyzed using METAL software, and the researchers then generated gene region plots of top SNPs using LocusZoom. The researchers used GTEx Portal to retrieve computed significant cis- and trans- expression quantitative trait loci from whole blood tissue tested in 168 samples.

Next, they confirmed the variants deemed highly prevalent in the first group by genotyping the DNA of an additional group of 159 African Americans, including 94 with VTE.

For this second round of genotyping, the researchers used the TaqMan allelic discrimination assay, and then performed the same analysis procedures.

They identified a link between VTE and three variants in a chromosome — rs2144940, rs2567617, and rs1998081 — associated with decreased expression of thrombomodulin, a protein that regulates clotting. Approximately 36 percent of American Americans have at least one of these variants, however, these variants were found in much lower frequency in other ethnicities from previous studies.

"This study not only brings us closer to understanding the cause of VTE in African Americans," Perera said in a statement, "it demonstrates the importance of conducting populations-specific research in precision medicine.

"Our next steps will involve investigating the predictiveness of these risk factors for VTE with the goal of reducing the high prevalence and burden of VTE in this disproportionately affected population," she said.