Study Provides New Molecular Insight into the Increased Risk of VTE in African Americans

African Americans are at a dramatically higher risk for developing venous thromboembolism (VTE), with a 30- to 60-percent higher risk than other ethnicities. The reasons behind this increased incidence are largely unknown, but the authors of a study published in Blood have found that certain genetic variants may be responsible for African Americans’ susceptibility to VTE.

Previous studies of white and European patients with VTE have identified specific genetic risk variants, prompting Wenndy Hernandez, PhD, from the Department of Medicine in the Section of Genetic Medicine at the University of Chicago, and colleagues to study whether genetic factors could also contribute to VTE risk in African Americans.

“Clinicians know that VTE is a multifactorial disease with genetics explaining only one piece of the risk,” Minoli A. Perera, PharmD, PhD, corresponding author of the study, told ASH Clinical News. “Our study shows that the genetic tests used clinically for VTE risk assessment are not informative for African Americans because, though they have a higher prevalence of the disease, they do not carry these genetic mutations as a population.”

Dr. Hernandez and investigators conducted a genome-wide association study that included a two-stage analysis of African-American patients with VTE: a discovery cohort followed by an examination of the most significant single nucleotide polymorphisms (SNPs) in an independent replication cohort.

Patients included in both parts of the study were unrelated, self-described as African-American, and were 18 years old or older. The following data related to potential risk factors for VTE were collected:

  • Age
  • Height
  • Weight
  • Ethnicity
  • Sex

Patients had a documented history of VTE (specifically proximal deep-vein thrombosis or pulmonary embolism) and did not have strong known risk factors such as prolonged hospitalization, surgery, active cancer or history of malignancy, pregnancy or puerperium, oral contraceptive use, menopausal replacement therapy, or protein C/S deficiency.

The discovery cohort included 146 patients with VTE and 433 controls, while the replication cohort had 94 patients with VTE and 65 controls.

In the discovery cohort, seven SNPs were identified that more than doubled the risk of VTE. The following SNPs reached genome-wide significance:

  • rs73692310 on chromosome 7 (odds ratio [OR] = 3.04; 95% CI 2.0-4.7; p=0.1.73×109)
  • rs58952918 on chromosome 18 (OR=2.48; 95% CI 1.7-3.7; p=1.07×10-8)
  • rs28496996 on chromosome 18 (OR=2.44; 95% CI 1.6-3.6; p=1.0×10-8)

The following SNPs also had a strong suggestive association with VTE risk:

  • rs2144940 on chromosome 20 (OR=2.18; 95% CI 1.6-2.9; p=3.52×10-7)
  • rs2567617 on chromosome 20 (OR=2.17; 95% CI 1.6-2.9; p=4.01×10-7)
  • rs1998081 on chromosome 20 (OR=2.28; 95% CI 1.6-3.1; p=5.17×10-7)
  • rs62322307 on chromosome 4 (OR=2.79; 95% CI 1.8-4.3; p=2.25×10-7)

“These risk alleles were found either almost exclusively or in higher frequency among populations of African descent,” wrote Dr. Hernandez and co-authors.

The subsequent replication study confirmed a significant association with increased risk of VTE for rs2144940 and rs1998081, while rs2144940 and rs1998081 reached genome-wide significance. These risk variants were found in higher frequency among populations of African descent (>20%) compared with other ethnic groups (<10%). “Together, these data support the association of rs2144940, rs2567617, and rs1998081 with increased risk of VTE among African Americans,” the authors concluded.

“Our newly discovered SNPs are common in African Americans, with one in three carrying at least one copy, and African Americans who carry this mutation have double the risk of VTE,” Dr. Perera told ASH Clinical News.

“We able to find a strong genetic predictor, and we were able to assign a function that makes biologic sense,” she added. Using bioinformatics analysis, Dr. Perera and colleagues found that these SNPs are associated with decreased thrombomodulin (THBD) gene expression – a regulator of the coagulation pathway in humans that inhibits clot formation – suggesting a mechanistic link between these genetic variants and increased VTE risk.

Though the study is limited by its small sample size, Dr. Perera noted that these results “have implications for personalized medicine. We need more discovery research in African Americans if they are to benefit from personalized medicine, as well.”

“This is the first study of its kind, so we need to follow up this work with a study to see if using this genotype can improve outcomes,” she added.


Hernandez W, Gamazon ER, Smithberger E, et al. Novel genetic predictors of venous thromboembolism risk in African Americans. Blood. 2016. [Epub ahead of print]