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Common genetic variants linked to high VTE incidence in black patients
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Genetic variants commonly found in black individuals may double their risk for venous thromboembolism, according to the results of a genome-wide association study published in Blood.
VTE is the third most common potential fatal cardiovascular condition. Compared with other ethnicities, black individuals are at a 30% to 60% increased risk for VTE, according to study background.
“While African Americans have a high risk for VTE, previous studies have not specifically focused on this population,” Minoli Perera, PharmD, PhD, associate professor of medicine at University of Chicago, said in a press release. “If we are not looking for the correct genetic mutations when we run a laboratory test, we are doing a disservice to minority populations.”
To better understand the mechanisms underlying population differences in VTE risk, Perera and colleagues conducted a genome-wide association study of black patients. The study included a discovery cohort of 146 patients with confirmed VTE (mean age, 54.9 ± 16.9 years) and 433 controls (mean age, 58.6 ± 16 years), as well as a validation cohort comprised of 94 patients with VTE (mean age, 59.3 ± 10.9 years) and 65 controls (mean age, 63 ± 16.4 years).
The researchers performed a bioinformatics analysis of top signals to identify expression quantitative trait loci (eQTL) in whole blood. They investigated mRNA expression differences between patients and controls.
The researchers identified and replicated three single nucleotide polymorphisms on chromosome 20 — rs2144940, rs2567617 and rs1998081 — that corresponded to a 2.3-fold increase in VTE risk (P < 6 x 10-7).
These risk variants predominated in populations of African descent compared with other ethnic groups (>20% vs. <10%). Further, approximately 36% of black patients harbored at least one of these risk variants.
Researchers used the GTEx Portal — which provides data on correlations between tissue-specific gene levels and genetic variation — to identify a biological function for the top SNPs associated with VTE risk.
Overall, rs1998081 appeared associated with differential thrombomodulin (THBD) gene expression in whole blood (P = 9 x 10-6). Thus, researchers identified the SNP rs1998081 as a cis-eQTL, or maps within 500 Kbs of the transcription start site, for THBD, a candidate gene of the coagulation pathway.
Further, THBD gene expression levels appeared significantly lower in patients with VTE (7.15 ± 0.59) compared with controls (7.61 ± 0.54; P adjusted for multiple testing = 4.31 x 10-5).
The researchers acknowledged the small sample sizes of the discovery and validation cohorts as a study limitation. Further, they acknowledged that there is a lack of genome-wide data in well-phenotyped black cohorts.
“This study not only brings us closer to understanding the cause of VTE in African Americans, it demonstrates the importance of conducting population-specific research in precision medicine,” Perera said. “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.” – by Cameron Kelsall
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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Nigel S. Key, MBChB, FRCP
Venous thromboembolism is an example of a disorder caused by multiple interacting genetic and environmental risk factors. The paper by Hernandez and colleagues addresses an important, and thus far understudied, problem. Clinical data have shown that VTE is more common in African Americans than in Americans of Anglo-European origin. Further, a positive family history of VTE (indicative of a genetic component) is equally prevalent in affected African Americans, despite that a causative mutation — especially the factor V Leiden and prothrombin G20210A mutations — are much less commonly identified in the black population. In this genome-wide association study of black patients with VTE, the researchers identified several markers on chromosome 20 in the vicinity of the gene for thrombomodulin, a cofactor in thrombin-dependent activation of protein C. These markers were two- to threefold more common in the black population and were associated with VTE risk.
Although it is biologically plausible that disruptive mutations in thrombomodulin could be associated with thrombophilia, this has yet to be proven. If prospective cohort studies validate the results of the Hernandez study, a greater understanding of the role of thrombomodulin mutations in VTE, especially in black patients, would represent an important advance.
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